An- Najah National University 

Faculty of Graduated Studies 

 

DESIGN, FORMULATION AND 

ANALYTICAL METHOD DEVELOPMENT OF  

CYCLOBENZAPRINE AND PARACETAMOL 

TABLET 

 

By 

Raghad Abd alraoof Lubbadeh 

 

Supervisors 

Prof. Abdel Naser Zaid 

Prof. Rowa’ Al Ramahi 

 

 

 

This Thesis is Submitted in Partial Fulfillment of the Requirements for the Degree of Master 

of Pharmaceutical Sciences, Faculty of Graduate Studies, An-Najah National University, 

Nablus- Palestine. 

 

2022 



II 

 
 



III 

 

Dedication 

All praise to Allah, with great respect and prayers through the days to help me to go 

forward in all difficulty every day a head. 

To the woman whom is like no other, she gave me life, held me and loved me 

unconditionally, to my affectionate Mother “Sanaa”, to the person who is my hero in the 

life who is giving without stop, be with me in all steps and stand me in the life up, the 

most important person in my life, my Father “Abd-Alraoof”. To my lovely supporting 

family and my loyal best friend. 

 

 

 

 

 

 

 

 

 

 

 

 

  



IV 

 

Acknowledgment 

At the beginning, all thanks to Allah for guiding me through every stage of this work, 

without his blessing it couldn’t have been accomplished the way it’s today. 

To my beloved parents, my brothers and sisters, to my family and best friends for 

supporting me spiritually throughout my life. 

Moreover, my sincere appreciation goes to the supervisors and monitors Professor Abd-

Alnaser Zaid and Professor Rowa Al Ramahi, for both their guidance and help in both 

academic and professional level.  I would like to thank the rest of my thesis committee. 

My sincere thanks also go to all staff of the Pharmacy department at An-Najah National 

University , as well as research and development department in local pharmaceutical 

companies PLC Pharm. and Dana pharm. company who were more than supportive in 

providing the equipment’s, materials and instruments needed for this research as well as 

scientific assistance from everyone in his field. Thanks to the Doctors  Dr. J.Ziyadeh 

and Prof. A.D.Alkilany for their significant scientific contribution.  

 

 

 

 

 

 

 

 

 

 



V 

 

Declaration 

  
I, the undersigned, declare that I submitted the thesis entitled: 

 

DESIGN, FORMULATION AND ANALYTICAL METHOD DEVELOPMENT 

OF CYCLOBENZAPRINE AND PARACETAMOL TABLET 

 

I declare that the work provided in this thesis, unless otherwise referenced, is the 

researcher’s own work, and has not been submitted elsewhere for any other degree or 

qualification. 

 

 

_____________________________________ Student's Name:  

_____________________________________ Signature: 

_____________________________________ Date: 

 

 

 

 

  



VI 

 

List of Contents 
 

Dedication ........................................................................................................................ II 

Acknowledgment ............................................................................................................ IV 

Declaration ....................................................................................................................... V 

List of Contents ............................................................................................................... VI 

List of Tables ............................................................................................................... VIII 

List of Figures ................................................................................................................. IX 

List of Appendices ........................................................................................................... X 

ABSTRACT .................................................................................................................... XI 

Chapter One: Introduction and Theoretical Background .................................................. 1 

1. Introduction ................................................................................................................... 1 

1.1 Pharmaceutical dosage forms ..................................................................................... 1 

1.2 Oral tablets .................................................................................................................. 1 

1.3 Pre-formulation and formulation ................................................................................ 2 

1.4 Quality control of tablets ............................................................................................ 3 

1.5 Stability testing ........................................................................................................... 3 

1.6 Validation .................................................................................................................... 4 

1.7 Muscle relaxants & Analgesic .................................................................................... 5 

1.8 Significance of the study ............................................................................................. 9 

1.9 Objectives of the study ............................................................................................. 10 

Chapter Two: Method ..................................................................................................... 11 

2. Materials & Method .................................................................................................... 11 

2.1 Materials and reagents .............................................................................................. 11 

2.2 Instruments ................................................................................................................ 11 

2.3 Formulation development and optimization ............................................................. 12 

2.4 Establishing stability indicating method ................................................................... 12 

2.5 Method ...................................................................................................................... 12 

2.5.1 Preformulation ....................................................................................................... 12 

2.5.2  Preparation of the formulation (Optimized Formula) ........................................... 14 

2.6 Pharmaceutical Quality Control ................................................................................ 14 

2.7 Validation of Assay .................................................................................................. 17 

2.8 Stability of tabletx ..................................................................................................... 19 

2.9 A pilot field study ..................................................................................................... 19 

2.9.1 Study design and setting ........................................................................................ 19 

2.9.2 Inclusion and exclusion criteria ............................................................................. 19 

2.9.3 Data collection and management ........................................................................... 20 



VII 

 

2.9.4 Ethical approval ..................................................................................................... 20 

2.9.5 Statistical analysis .................................................................................................. 20 

Chapter Three: Results .................................................................................................... 21 

3. Results ......................................................................................................................... 21 

3.1 Preformulation Testing ............................................................................................. 21 

3.1.1 Compatibility & flow properties ............................................................................ 21 

3.1.2 Water Content/LOD Determination ....................................................................... 21 

3.1.3 Excipients and APIs Compatibility........................................................................ 22 

3.2 Preparation of the formulation (Optimized Formula) ............................................... 22 

3.3 Evaluation of Compressed Tablets ........................................................................... 23 

3.4 Validation/Verification Results ................................................................................ 26 

3.5 Stability Study Results .............................................................................................. 30 

3.6 The pilot observation clinical study .......................................................................... 32 

Chapter Four: Discussion and Conclusion ...................................................................... 43 

4. Discussion and conclusion .......................................................................................... 43 

4.1 Conclusion ................................................................................................................ 44 

List of Abbreviations ...................................................................................................... 45 

References ....................................................................................................................... 47 

Appendices ...................................................................................................................... 50 

 ب‌ ............................................................................................................................... انًهخص

 

 

 

 

 

 

 

 

 

 



VIII 

 

List of Tables 
 

Table 1: API& Excipients Water content (WC)/loss on drying (LOD) Results ............. 21 

Table 2: Compatibility Testing Results. ......................................................................... 22 

Table 3: Tablets Optimized Formula. ............................................................................. 23 

Table 4: Tablets parameters (length, thickness & hardness). ......................................... 23 

Table 5: Weight Variation Results. ................................................................................. 24 

Table 6: Assay Results. ................................................................................................... 26 

Table 7: Assay Linearity Results for Paracetamol & Cyclobenzaprine HCl .................. 27 

Table 8: Assay Precision Results. ................................................................................... 29 

Table 9: Assay Accuracy/Recovery Results for paracetamol. ........................................ 30 

Table 10: The result of stability listed in the following table ......................................... 31 

Table A.1: General stability storage conditions .............................................................. 50 

Table A.2: Scale of Flowability ...................................................................................... 50 

Table A.3: API& Excipients Water content (WC)/loss on drying (LOD) ...................... 50 

Table A.4: (API: Excipients) Ratios for Compatibility Test. ......................................... 51 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 



IX 

 

List of Figures 

 

Figure 1: Cyclobenzaprine HCl (A) & Acetomenophine (B)  chemical structures .......... 8 

Figure 2: Linearity of Assay for paracetamol. ................................................................ 28 

Figure 3: Linearity of Assay for Cyclobenzaprine HCl. ................................................. 28 

Figure 4: Doctors’ questionnaire results (N =50) ........................................................... 33 

Figure 5: Patients’ questionnaire results (N=30) ............................................................ 37 

 

 

 

 

 

 

‌  



X 

 

List of Appendices  
 

Appendix A: Tables of Study ......................................................................................... 50 

Appendix B: Data collection form .................................................................................. 52 

Appendix C: IRB approval ............................................................................................. 58 

Appendix D: Chromatogram results ............................................................................... 59 

 

 

 

 

  



XI 

 

DESIGN, FORMULATION AND ANALYTICAL METHOD DEVELOPMENT 

OF CYCLOBENZAPRINE AND PARACETAMOL TABLET 
 

By 

Raghad A. Lubbadeh 

Supervisors 

Dr.Abdel Naser Zaid 

Dr. Rowa’ Al Ramahi 
 

ABSTRACT 

Background: Cyclobenzaprine HCl is a muscle relaxant, and Paracetamol is a pain relief 

drug. There are many indications for the co-administration of both medications. The aim of 

this project was to formulate and evaluate the stability of a novel tablet containing 

Cyclobenzaprine HCl and Paracetamol together. Moreover, a new fully validated and 

stability indicating HPLC method was developed to test the stability of the obtained 

product.  

Method: The Cyclobenzaprine HCl and Paracetamol novel tablet formula was optimized 

and selected according to several critical quality attributes (CQAs), including assay, 

content uniformity, dissolution, and degradation profiles. Method development it’s 

validation included linearity and range, accuracy and recovery, precision, specificity and 

stress conditions. Moreover, tablet stability was evaluated after 3 and 6 months under 

different storage conditions. A pilot study was conducted among doctors and patients to 

evaluate their opinions and acceptance of this combination. 

Results:  Successfully formulated tablets, including 5 mg Cyclobenzaprine and 500 mg 

Paracetamol, were uniform in weight, with an average tablet weight of 650 mg. All product 

quality parameters were within specifications, including those for critical and non-critical 

quality attributes. A fully validated and stability-indicating method was established for 

assay and dissolution testing. The developed method exhibited high linearity with an R2 of 

more than 0.98 precision with a relative standard deviation of less than 2% and an accuracy 

result of between 98.0 and 102% for Cyclobenzaprine HCl and Paracetamol. The prepared 

Cyclobenzaprine HCl and Paracetamol tablets showed excellent stability over 6 months. 

The findings of the pilot field study provided insight into the acceptance of the 

combination of both drugs by doctors and patients.  



XII 

 

Conclusion: Cyclobenzaprine HCl and Paracetamol tablets were successfully formulated 

and showed an acceptable stability profile. The developed and validated HPLC method 

was suitable for the characterization and assessment of the formulated tablets. The novel 

combination is likely to be accepted by doctors and patients. 

Key words: Cyclobenzaprine, Paracetamol, Formulation, Validation, Tablets. 



 

 

Chapter One 

Introduction and Theoretical Background 

1. Introduction 

1.1 Pharmaceutical dosage forms 

Pharmaceutical dosage forms are drug products composed of a single or a combination 

of Pharmaceutical Active Ingredient/s (APIs) and a group of inactive ingredients 

(excipients) available in the pharmaceutical market to serve dosing, administration  and 

delivery according to patients’ needs (1, 2). 

All steps regarding formulation, design, processing, evaluation, and achieving high 

target finished product quality (chemically, physically, biologically and route of 

administration) are important (3). 

Pharmaceutical dosage forms can be classified according to their route of administration 

such as: parenteral, mucosal, inhalation, topical/dermal and gastrointestinal or according 

to their pharmaceutical dosage form such as: aerosols, capsules, creams, foams, gels, 

ointments, tablets, suppositories, lozenges, suspensions, injections and  sprays…etc, or 

according to their release pattern such as: immediate release and modified release which 

may include: delayed release or sustained release, ..etc. (4-7) 

1.2 Oral tablets 

Tablets are the most frequent and favorable route of administration of solid dosage 

forms; which offer the patients drug stability and dosing reproducibility. Some tablets 

are swallowed whole as it is; others can be chewed before swallowing, some are 

dispersed or dissolved in water before administration, while some allows liberation of 

active substance by retaining it in the mouth (8). Tablets are single dose compose of one 

or more of active materials, obtained by using a suitable manufacturing technique to 

compress a uniform volume of particles with excipients; that act as binders, diluents, 

lubricants, fillers, disintegrating agents, glidants, behavior modifiers, coloring agents… 

etc. Tablets can be produced in different sizes and shapes. Classified into immediate 

release and modified release if a change in release rate  is made (4). 



2 

 

Several techniques combining art and science can be used in order to produce tablets 

that have specific odor, taste, shape, release pattern and function (1, 8, 9). Tablets can 

be categorized into: (coated tablets, uncoated tablets, gastro-resistant tablets,  soluble 

tablets, modified release tablets, effervescent tablets, dispersible tablets, oral dispersed 

tablets, oral lyophilisates and chewable tablets) (1). 

In addition to the APIs, tablets contain excipients. Excipients are needed to bulk the 

actives, to help in compression or to modify the biopharmaceutical properties of the 

tablet. Examples to add bulk fillers are used, granule and compact. Formation needs 

binders to allow tablet to break down in the body fluid, disintegrants are used for 

dissolution particularly for hydrophobic API, wetting agents are need to reduce the 

friction between powder and dies, lubricants are used, anti-adherents prevent sticking 

between powder material and surfaces of the compression tooling, for good powder 

flowability glidants and fillers are needed which can modify the API release from the 

tablet. All these excipients can work to affect properties of the final tablet and 

compression. (10) 

1.3 Pre-formulation and formulation 

Pre-formulation is considered as the first step to be followed for sensible dosage forms 

development; by which total investigation of the drug substance properties (Physical, 

Chemical) and its compatibility with excipients is made (11). Pre-formulation aims 

mainly to give well prospective of stable dosage forms with good bioavailability that 

can be also manufactured in large scale. To make a successive pre-formulation program, 

corporation of experts of different disciplines is needed. The pre-formulation program 

starts with the assessment of the organoleptic properties of the new drug (odor, color & 

taste), purity of the drug substance, chemical and physical properties of the drug 

substance which is affected by the particle size distribution, particles shape, solubility, 

dissolution and determining the parameters that will affect absorption of the drug 

substance, polymorphism etc. (11). 

Formulation based on Quality by Design (QbD) is a risk assessment-based approach 

used to develop both brand and generic products. This approach depends mainly on 

defining the quality target product profile (QTPP) according to drug substance 

characteristics, reference listed drug (RLD) properties and label, in addition to the 



3 

 

patients targeted by this developed product. QTPP can be achieved by defining the 

critical quality attributes (CQA) based on the safety and efficacy of the product 

delivered to the patients (12).  

Employing QbD approach parameters in any proposed formulation may help in 

establishing a quality control strategy of manufacturing parameters and changes, which 

produce\s a product with high quality monitored during its lifecycle based on risk 

assessment (12). 

1.4 Quality control of tablets 

Formulated tablets should be evaluated to guarantee an effective dosage form within the 

accepted requirements. Evaluation is typically done via several physical and chemical 

testing (13, 14), which include but not limited to,description, identification, assay of 

active ingredient, uniformity of dosage units, hardness, friability, dissolution, and 

disintegration. 

1.5 Stability testing 

Stability means the extent or the level to which the drug product or drug substance 

remains within approved  specifications throughout its storage period (15).  The main 

aim of stability testing is to give obvious evidence of drug substance or a drug product 

behavior under the influence of several environmental factors with time and how it may 

impact its quality of the pharmaceutical formulation. 

Stability testing is considered as a mandatory requirement for pharmaceutical dosage 

forms as it helps in avoiding any ingredient or condition that causes chemical 

decomposition and/or physical or microbiological deterioration of the drug products or 

materials. Stability testing includes determination of the content of active ingredient, 

degradation products, physical properties and appearance, in addition to other properties 

such as (moisture content, hardness, friability, dissolution, and disintegration). 

According to these parameters, stability is classified into five types: (chemical, physical, 

microbiological, therapeutic and toxicological). The main environmental parameters 

that influence the drug stability are exposure to adverse temperature, excessive 

humidity, light, oxygen etc. (15). 

 



4 

 

Stability is considered as an important evidence of the drug product or a certain formula 

quality variation under different environmental factors (as temperature and humidity) 

with time and it is an important tool in establishing the shelf life or retesting period of 

the drug product and its most appropriate storage conditions (14). 

Testing conditions are selected according to the climatic zone for each country. But the 

general case is listed in Table (No.1). 

Stability general storage conditions were attached in Appendix A table 1. 

1.6 Validation 

Analytical method is a description of the detailed steps of how to perform tests for 

evaluating the drug product quality (13, 16). Validation of analytical method is intended 

to prove that it is suitable for the intended purpose. It  includes full assessment of the 

sample, reagents, apparatus, standards, analytical conditions, preparation, changing 

analyst, and even the time of preparation (17). 

Validation parameters including: Specificity /Selectivity, Accuracy, Precision, 

Linearity, Range, Robustness and Stress Conditions (17). 

 Accuracy: is the measure of closeness of measured value to the true value at a 

prescribed condition. 

 Precision: is the measure of closeness of a series of measurements at prescribed 

conditions. It is measured in three levels (repeatability which expresses precision at 

the same operating conditions during short time, reproducibility which means 

precision between laboratories, and intermediate precision which means precision 

within laboratory variations as different analysts and days).  

 Linearity: it is the ability of method to give direct proportional response to 

concentration, which expressed by using linearity regression Coefficient (R
2
). 

 Range: is the interval between upper and lower limits of concentrations or amounts 

of the sample analyte which achieves suitable levels of accuracy, precision, and 

linearity within these limits. 



5 

 

 Robustness: it is the ability of method to be unaffected by small and deliberate 

changes of conditions and parameters under normal conditions(17). 

 Selectivity and Specificity: it is the measure of procedures ability to assess the 

effect of components on the analyte, these components might be impurities, 

degrades, or matrix. It is determined by chromatographing the matrix and solvents 

rather than the analyte. 

 Limit of Quantitation (LOQ): It is the lowest amount of analyte in a sample that can 

be determined with acceptable Precision and Accuracy under the stated 

experimental conditions. 

 Limit of Detection (LOD): It is the lowest amount of analyte in a sample that can be 

detected with confidence and distinguished from noise/baseline, but not necessarily 

quantitated, under the stated experimental conditions (16, 17). 

 Stress testing of the drug substance helps in potential degradation products 

identification, that helps in establishing the degradation pathway. It is also used as a 

tool for indicating power of the used analytical procedures(18). Stress testing 

includes effect of high temperatures above that of the accelerated conditions, 

humidity, oxidation, photolysis and evaluation of hydrolysis over a wide pH range 

(acidic and basic) conditions (19). 

Any change in the analytical procedure, drug substance synthesis and composition of 

finished product; needs revalidation. However it depends on the change degree and its 

nature (13, 20). 

1.7 Muscle relaxants & Analgesic 

Low back pain is associated with considerable suffering and disability linked to a range 

of symptoms, including tingling or burning, dull ache, sharp pain, and weakness in the 

legs or feet. Back pain is among the most common reasons patients visit their primary 

care physicians. A plethora of effective treatment options are available. (21)  

 

 



6 

 

These range from pharmacologic measures (eg, analgesics, anti-inflammatory 

medications, muscle relaxants and steroid injections) to non-pharmacologic approaches 

(eg, bed rest, massage therapy, exercise, application of heat or ice, acupuncture and 

spinal manipulation). (21, 22) 

Analgesics such as Acetaminophen and non-steroidal anti-inflammatory drugs 

(NSAIDs) have often been used as first-line agents for controlling the symptoms of low 

back pain which should be taken at the maximum anti-inflammatory dose (ie, ibuprofen 

600-800 mg TID, for more than two weeks). Cyclooxygenase (COX)-2 selective 

inhibitors do not offer analgesic benefit over traditional NSAIDs and are indicated only 

for patients at risk for gastrointestinal bleeding. (21) 

Although analgesic pain management may be the treatment of first choice, relief from 

low back pain may also require alleviation of muscle spasm with oral muscle relaxants. 

Muscle relaxants as (Carisoprodol, orphenadrin, cyclobenzaprine hydrochloride, and 

metaxalone) can be used as monotherapy or in combination with analgesics  for patients 

with low back pain.(21) 

Paracetamol and Orphenadrine combination as a muscle relaxant combined with 

analgesic drug available as oral tablet under the trade name (Relaxone tablet, Beit jala 

pharmaceutical) is used to relieve pain and stiffness caused by muscle strains and 

sprains. In fact it is indicated for the relief of severe skeletal muscle spasms associated 

with painful conditions such as low back pain, sprains and strains.  

Skeletal muscle relaxants are a heterogeneous group of medications commonly used to 

treat two different types of underlying conditions: spasticity from upper motor neuron 

syndromes and muscular pain or spasms from peripheral musculoskeletal conditions 

(23). 

Common musculoskeletal conditions causing tenderness and muscle spasms include 

fibromyalgia, tension headaches, myofascial pain syndrome, and mechanical low back 

or neck pain. If muscle spasm is present in these conditions, it is related to local factors 

involving affected muscle groups. These conditions are commonly encountered in 

clinical practice and can cause significant disability and pain in some patients. Skeletal 



7 

 

muscle relaxants are one of several classes of medications frequently used to treat these 

conditions (23). 

Benzodiazepines like tetrazepam are used as anxiolytics, hypnotics, sedatives 

anticonvulsants or skeletal muscle relaxants. Generally there is no evidence that any one 

benzodiazepine is more effective than another if enough dosage is taken; as a result, 

pharmacokinetic differences between the drugs may be important considerations in 

prescription choice.(24) 

Non-benzodiazepines include a variety of drugs like Cyclobenzaprine that can act at the 

brain stem or spinal cord level.(24) 

Cyclobenzaprine hydrochloride has been recommended as an adjunct to rest and 

physiotherapy for the relief of muscle spasm associated with acute, painful 

musculoskeletal conditions. At therapeutic doses, the compound does not affect central 

nervous system (CNS) function. As a result, it depresses motor neuron hyperactivity 

without significant ataxia and is ineffective in muscle spasm caused by CNS disease 

(23). 

Cyclobenzaprine is in a class of medications called skeletal muscle relaxants. It works 

by acting in the brain and nervous system to allow the muscles to relax. 

Cyclobenzaprine is used for short time together with rest and physical therapy to 

treat skeletal muscle conditions such as pain or injury (25).  

Chemically defined as N, N- dimethy l- 3- (2- tricycle [9.4.0.03,8] pentadeca-

1(15),3,5,7,9,11,13-heptaenylidene) propan-1-amine (26). 

Cyclobenzaprine is a centrally acting skeletal muscle relaxant with antidepressant 

activity. The exact mechanism of action of cyclobenzaprine has not been fully 

determined, but this drug seems to primarily act at the brain stem to reduce tonic 

somatic motor activity, influencing both gamma and alpha motor neurons leading to a 

reduction in muscle spasms (26). 

Cyclobenzaprine blocks tonic α-motoneuronal excitation produced by serotonergic 

descending neurons. The blockade of 5-HT 2 receptors to be the major action of 

cyclobenzaprine as muscle relaxant. (27) 

https://www.drugs.com/cg/muscle-strain.html


8 

 

The oral bioavailability of cyclobenzaprine has been estimated to be between 0.33 and 

0.55. maximum concentration (Cmax) is between 5-35 ng/mL and is achieved after 4-

hours maximum time (Tmax). AUC over an 8-hours dosing interval was reported to be 

approximately 177 mg.hr/mL. Orally administered Cyclobenzaprine HCl is well 

absorbed. Cyclobenzaprine HCl undergoes enterohepatic circulation, and appears to be 

metabolized by both oxidative and conjugative pathways during its first pass through 

the gastro intestinal (GI) tract and/or liver. Mean oral bioavailability of the drug is 

estimated to range from 33-55% (26). 

The common Cyclobenzaprine HCl oral tablet side effects may include: drowsiness, 

tiredness, headache, dizziness, dry mouth, upset stomach, nausea, constipation (28). 

The following figure show the chemical structure of Cyclobenzaprine HCl: 

Figure 1  

Cyclobenzaprine HCl (A) & Acetomenophine (B)  chemical structures 

 

 

 
 

Acetaminophen (Paracetamol) is the most commonly used analgesic worldwide and is 

recommended as first-line therapy in pain conditions by the World Health Organization 

(WHO). 

It is also used for its antipyretic effects, helping to reduce fever. This drug was initially 

approved by the United States food and drug administration (U.S. FDA) in 1951 and is 

available in a variety of forms including syrup form, regular tablets, effervescent tablets, 

A 

 

B 

 

https://www.drugs.com/cg/acute-headache.html
https://www.drugs.com/cg/vertigo.html
https://www.drugs.com/cg/acute-nausea-and-vomiting.html
https://www.drugs.com/cg/constipation.html
https://www.sciencedirect.com/topics/medicine-and-dentistry/paracetamol


9 

 

injection, suppository, and other forms. Acetaminophen is often found combined with 

other drugs in more than 600 over the counter over the counter (OTC) allergy 

medications, cold medications, sleep medications, pain relievers, and other products 

(26). 

Chemically defined as N-(4-hydroxyphenyl) acetamide & molecular formula is 

C8H9NO2 (26). 

Acetaminophen is mainly metabolized in the liver by first-order kinetics, about 80-85% 

of the acetaminophen in the body undergoes conjugation principally with glucuronic 

acid and to a lesser extent with sulfuric acid. Overdoses of acetaminophen can lead to 

hepatic necrosis due to the depletion of glutathione and of binding of high levels of 

reactive metabolite (NAPQI) to important parts of liver cells (25, 26).  

Acetaminophen has 88% oral bioavailability and reaches its highest plasma 

concentration 90 minutes after ingestion. Peak blood levels of free acetaminophen are 

not reached until 3 hours after rectal administration of the suppository form of 

acetaminophen and the peak blood concentration is approximately 50% of the observed 

concentration after the ingestion of an equivalent oral dose (10-20 mcg/mL) and it is 

rapidly and almost completely absorbed from the GI tract following oral administration 

(26). 

The following figure shows the chemical structure of Paracetamol: 

1.8 Significance of the study 

The main aim for any formulated drug is patient. The idea was to design a tablet that 

contains two active ingredients in the same tablet core instead of taking two tablets 

separately; this may be easier for the patient and improve compliance with treatment. 

Paracetamol and Orphenadrine Citrate is the only formulation on the market that 

contains both paracetamol and a muscle relaxant. The combined is used to improve 

patients compliant especially the elderly patients & pregnant women as a safe drug for 

them and which is good as to have a rapid result from the drug as analgesic then as 

muscle relaxant and patient & companies will save money when they found these drug. 

The suggested formulation in this study includes paracetamol and cyclobenzaprine HCl. 

https://www.sciencedirect.com/topics/medicine-and-dentistry/paracetamol
https://pubchem.ncbi.nlm.nih.gov/compound/glucuronic%20acid
https://pubchem.ncbi.nlm.nih.gov/compound/glucuronic%20acid
https://pubchem.ncbi.nlm.nih.gov/compound/sulfuric%20acid


01 

 

Because this formulation was not available in our marker, we needed to develop and 

validate an analytical method  

1.9 Objectives of the study 

The aim of this project is to formulate and evaluate novel combination of 

Cyclobenzaprine HCl and Paracetamol (oral tablet). 

Specific objectives 

1. Formulation and examination of the mixed powder compressed tablet drug.  

2. Development and validation of analytical method to be used for testing the active 

ingredient in the product (Assay). 

3. Full assessment of the finished product characterization and specifications for all 

physical and chemical parameters. 

4. A pilot study questionnaire to collect doctors’ and patients’ perspectives regarding 

combining Paracetamol and Cyclobenzaprine HCl into a single tablet. 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 



00 

 

Chapter Two 

 Method 

2. Materials & Method 

2.1 Materials and reagents 

pharma grade Cyclobenzaprine HCl raw material (Vasudha manufacturer, India) was 

provided by Pharmacare PLC (Ramallah, Palestine) and Paracetamol (merck 

manufacturer, Germany) from the An-najah University laboratories. Cyclobenzaprine 

HCl (Xaprine 5 or 10 mg) and Paracetamol (Panadol 500 or 1000 mg) products found in 

the Palestinian pharmaceutical market were used. Solvents such as Acetonitrile, Water 

and Methanol (were provided from the university and Dana Pharm, provided from 

Honeywell (USA, HPLC grade). Other reagents and chemicals used in this study; 

sodium starch glyconate, magnesium stearate and Avicel 101 were from Pharmacare 

PLC. Ammonium acetate (sigma Aldrich manufacturer), sodium hydroxide (Gadot 

manufacturer) and acetic acid (Gadot manufacturer) were provided from the university 

and Dana Pharmaceutical Company.  

2.2 Instruments 

High-performance liquid chromatography 

High-performance liquid chromatography (HPLC) is an instrument used to analyze 

material using analytical method to distinguish, separate and quantify each ingredient in 

a mixture. The system of HPLC used in this study is Hitachi Lachrom Elite HPLC, with 

(2 - 4.6) mm internal diameter, columns for liquid chromatography (LC) and flow-rate 

range of (0.00 -10.00) mL/min in 0.01 mL increments, column temperature in the range 

of (20 – 60) °C was controlled using attached column heater. 

Dissolution apparatus 

Dissolution tests were performed to determine the rate and extent of drug release from 

prepared drug formulations. Dissolution tester (Hsiang Tai machinery industry, Taiwan, 

China) was used in all dissolution testing. Dissolution Apparatus 2 Paddle with six 

vessels each of them filled with 900 ml of dissolution media was used. Paddle speed 

was fixed to 50 rpm. The quantity of dissolved API(s) was determined using UV visible 



02 

 

spectroscopy (Shimadzu, Japan, UV 1280 spectrophotometer) which offers 190-1100 

nm wavelength scanning. 

2.3 Formulation development and optimization 

The work plan includes the determining all physicochemical properties of 

Cyclobenzaprine HCl and Paracetamol mixed powder tablets and performing all 

required pre-formulation studies. Cyclobenzaprine HCl and Paracetamol mixed powder 

tablets were formulated by using fixed dose of Cyclobenzaprine HCl 5 mg/tablet and 

500 mg/tablet of Paracetamol. Pharmaceutical excipients were selected based critical 

quality parameters and required final specifications of the oral tablets. Types and 

quantities of excipients were determined based on their compatibility and typical used 

levels for each with optimization. Tablets were produced using direct compression 

technique. Physical properties, hardness, dimensions of tablets, appearance and 

friability were tested for the obtained oral tablets. 

2.4 Establishing stability indicating method 

Stability indicating method relied on assay test of Cyclobenzaprine HCl and 

Paracetamol drug substance using stress conditions for drug degradation as listed in 

ICH and USP. 

The degradation of tablet was demonstrated using: Acid Degradation (1M HCl), Base 

Degradation (1M NaOH) & Oxidation (3% H2O2) (16) 

2.5 Method 

2.5.1 Preformulation 

Prior to processing, powder properties were determined by measuring the powder inter-

particulate interactions (14). 

Bulk Density   

Mass of powder taken (m) and volume of untapped powder (Vi) were measured to 

calculate: Bulk density = m/Vi  

 



03 

 

Tapped Density 

Mass of powder (m) Tapped volume (Vt) were measured to calculate: 

Tap density = m/Vt  

Compressibility Index  

 

Hausner Ratio 

 

The flow ability scale of the powder with Hausner ratio were attached in appendix A 

table 2. 

Water Content/LOD Determination 

Water content/LOD of the API and each excipient used in the formulation was tested 

according to its testing procedure in the pharmacopeias (11); as illustrated in Table (3) 

in appendix A. 

Excipients and APIs Compatibility 

A high-quality, safe, and effective drug product is the main target of any formulation. 

Not only during manufacturing, but also after long-term use; to ensure this before 

beginning the formulation, a compatibility study between API and excipients is 

recommended, which is considered a limiting step in any successful formulation and 

ensures that no impact of any used excipient on the API characteristics and properties, 

because any change in appearance, quantitative parameters, physical and chemical 

properties gives evidence of a lack of opacity. This, in turn, leads to risk and a direct 

impact on the product's quality and safety. 

Intended used excipients were mixed with API in optimized quantities (as listed in 

Table 4 Appendix A) and stored at 40°C and 75% RH for 30 days, and then every 

portion was analyzed for appearance, flowability and assay (using Assay Method).  



04 

 

2.5.2  Preparation of the formulation (Optimized Formula) 

After thoroughly testing the compatibility, physical and chemical properties, function, 

and test/odor characteristics of each component of the formulation, we evaluated 

mixtures. Many formulation trials were initiated to reach the best one. 

2.6 Pharmaceutical Quality Control 

The prepared tablets were visually inspected for general appearance such as shape, 

color, or any other physical defect. In addition, to assure pharmaceutical quality of the 

tablets other pharmacopeial quality control tests were performed including friability of 

tablets, hardness of the tablet, weight uniformity, assay, disintegration time and 

dissolution.   

I. Assay 

Assay of tablet product was assessed according to USP monographs. In-house method 

trial done at the university and Dana Pharm Company for drug analysis was employed 

in this research under their permission.  

T Mobile phase composition, mobile phase gradient, wavelength, column and flow rate 

were the parameters that were optimized to reach the following final method of 

analysis. 

The final used test method 

Mobile phase: a mixture of 650 ml of buffer (11.4 g/L ammonium acetate in water with 

pH adjustment to 7.2 using ammonium hydroxide) and 350 ml methanol then it was 

filtered through 0.45 micro membrane filtered. 

Diluent: same as mobile phase. 

Standard preparation:  

Standard solution 1: an accurate weight quantity in 100 ml volumetric flask (VF) of 500 

mg Cyclobenzaprine HCl WS was dissolved with diluent to 100 ml. 

Standard solution 2: an accurate weight quantity in 100 ml VF of 50 mg 

Cyclobenzaprine HCl WS was dissolved with diluent to 100 ml. 



05 

 

Standard solution: dilute 1 ml of standard solution 1 and 10 ml of standard solution 2 in 

100 ml with diluent to obtain a concentration of 0.005 mg/ml of Cyclobenzaprine HCl 

and 0.5 mg/ml of paracetamol, stir and filtrate with 0.45 µm syringe filter. 

Sample preparation: transfer not less than 10 tablet to a suitable mortar to crush into a 

powder, transfer accurately amount of powder equivalent to weight of one tablet to 100 

ml VF and dilute to 100 ml with diluent, stir for 10 min to dissolve to prepare sample 

stock solution. Dilute 10 ml of sample stock solution to 100 ml with diluent to obtain a 

concentration of 0.005 mg/ml of Cyclobenzaprine HCl and 0.5 mg/ml of paracetamol, 

stir and filtrate with 0.45 µm syringe filter. 

Chromatographic system: 

Column: C8 (Octyl) HPLC Column 25cm x 4.6mm 5µm, L7, Column temperature: 

30ºC, Detector wavelength: 226 nm, Flow rate: 1 ml/min, Injection volume: 15 µL. 

 The percentage of the Cyclobenzaprine HCl & Paracetamol content in the tablet 

compared to the standard was measured using the following equation:  

%Asssy = ("rt" /"rs")*("Ct" /"Cs" )* STD Potency *100 

Where: 

rt: sample solution Peak area response. 

rs: standard solution peak area response. 

Cs: standard solution concentration (mg/ml). 

Ct: sample solution concentration (mg/ml) 

II. Weight uniformity test 

To evaluate the weight uniformity of tablets, 20 tablets were randomly picked out and 

weighed individually using an analytical weighing balance. The average weights for 

each product and the percentage relative standard deviation were calculated according 

to USP test of weight uniformity.  

 



06 

 

III.  Hardness and friability    

To assess the crushing strength of tablet products the hardness test performed, 10 

formulated tablets were randomly selected to measure the hardness using the hardness 

tester. 

IV. Disintegration  

To assess the disintegration time of tablet, 6 tablets were placed in a disintegrator which 

consists of a basket with 6 tubes. The basket loaded with the tablets was immersed in a 

bath of water and the temperature was 37°C. The disintegration time of the tablets was 

noted when it completely disappeared (disintegrated) and no stacked particles were left 

on the mesh of the basket of the disintegrator.     

V. Dissolution  

The dissolution of tablet products calculated by preparing a standard solution which was 

used to establish the different products dissolution profile, 0.0055 mg/ml of 

cyclobenzaprine and 0.55 mg/ml of paracetamol were prepared in dissolution medium 

acetate medium (acetate buffer, pH 4.5 per one litter dissolve 5.9 g of sodium acetate 

and 7.4 ml of Acetic acid and pH adjust with sodium hydroxide). To prepare the sample 

solution, six tablets were tested using USP Dissolution Apparatus 2 Paddle, 900 ml of 

dissolution medium was added to each vessel and the temperature was maintained at 37 

± 0.5 °C. One tablet was placed in each of the dissolution vessels with a paddle stirrer at 

50 rpm. At the end of 30 minutes, sample aliquots (5 ml) were withdrawn from a zone, 

filtered using a 0.45 µm filter syringe. The filtered sample was tested in comparison 

with standard by ultra violet (UV) spectroscopy at wavelengths of 290 nm and 250 nm 

for Cyclobenzaprine HCl and Paracetamol, respectively. 

The percentage of the content in the pharmaceutical products compared to the standard 

was calculated using the following equation: 

% Recovery = ( AT/AS)*(CT/CS)* STD Potency (%) 

AT: Sample solution absorption. 

AS: Standard solution absorption  

Cs: Standard solution concentration (mg/ml). 



07 

 

CT: Sample solution concentration (mg/ml).    

2.7  Validation of Assay 

The following validation tests were performed (16), the results were compared with the 

requirements of the Palestinian Ministry of Health according to Word Health 

Organization. 

I. Linearity and Range  

Mobile phase: a mixture of 700 ml of buffer (11.4 g/L ammonium acetate in water with 

pH adjustment to 7.2 with ammonium hydroxide) and 350 ml methanol then it was 

filtered through 0.45 micro membrane filter. 

Diluent: Same as Mobile phase. 

Paracetamol standard stock solution of 5 mg/ml and Cyclobenzaprine HCl standard 

stock solution of 0.05 mg/ml were used for preparation of subsequent aliquots; aliquots 

of 0.2, 0.225, 0.25, 0.275, 0.3, 0.4, 0.45, 0.5, 0.55 and 0.6 mg/mL concentrations were 

prepared by serial dilution for Paracetamol and aliquots of 0.002, 0.00225, 0.0025, 

0.00275, 0.003, 0.004, 0.0045, 0.005, 0.0055 and 0.006 mg/mL concentrations were 

prepared by serial dilution for Cyclobenzaprine HCl. The solution of 2 mL was loaded 

in autosampler tray and 15 μL was being injected into column. All measurements were 

repeated three times for each concentration. The calibration curves of the area under 

curve versus concentration were recorded. 

Acceptance criteria: R
2
 is NLT 0.98. 

II. Precision 

Standard solution (conc. 0.5 mg/ml Paracetamol & 0.005 mg/ml Cyclobenzaprine HCl) 

was injected into the chromatogram six times; RSD was calculated. 

Acceptance criteria: (RSD should be NMT 2.0 %). 

 

 

 



08 

 

III. Accuracy and Recovery 

Sample Solution: 3 aliquots were prepared from each concentration as following:  

116 mg placebo were mixed with 400 mg paracetamol & 4 mg Cyclobenzaprine HCl 

dissolved in 100 ml diluents; sonicated for 5 min; cooled to room temp. Then volume 

completed to 100 ml with diluents, 10 ml of obtained solution was diluted to 100 ml 

with diluents (conc. 0.4 mg/ml paracetamol & 0.004 mg/ml Cyclobenzaprine HCl). 

145 mg placebo were mixed with 500 mg paracetamol & 5 mg Cyclobenzaprine HCl 

dissolved in 100 ml diluents; sonicated for 5 min; cooled to room temp. Then volume 

completed to 100 ml with diluents, 10 ml of obtained solution was diluted to 100 ml 

with diluents (conc. 0.5 mg/ml paracetamol & 0.005 mg/ml Cyclobenzaprine HCl). 

174 mg placebo were mixed with 600 mg paracetamol & 6 mg Cyclobenzaprine HCl 

dissolved in 100 ml diluents; sonicated for 5 min; cooled to room temp. Then volume 

completed to 100 ml with diluents, 10 ml of obtained solution was diluted to 100 ml 

with diluents (conc. 0.6 mg/ml paracetamol & 0.006 mg/ml Cyclobenzaprine HCl). 

Procedure: 15 µl of each prepared sample and standard solution were injected into the 

chromatogram, % Recovery was calculated for each injected sample. 

Acceptance criteria:  ± 2.0 %. 

IV. Specificity 

40 ml of diluent added to 145 mg placebo; sonicated for 5 min and cooled to room 

temperature, then volume completed to 100ml with diluent; 10 ml of obtained solution 

was diluted to 100 ml with diluent. 15 µl were injected, in the chromatogram obtained it 

should show no signals at the retention time of paracetamol and Cyclobenzaprine HCl 

peaks. 

V. Stability Indicating Method (Stress Conditions) 

Base Degradation (NaOH): 5.0 ml of SSS1, 5.0 ml of SSS2 & 5.0 ml of 1M NaOH 

solution were diluted to 50 ml with diluents. (Conc. 0.55 mg/ml paracetamol & 0.0055 

mg/ ml Cyclobenzaprine HCl).  



09 

 

Acid Degradation (HCl): 5.0 ml of SSS1, 5.0 ml of SSS2 & 5.0 ml of 1M NaCl 

solution were diluted to 50 ml with diluents. (Conc. 0.55 mg/ml paracetamol & 0.0055 

mg/ ml Cyclobenzaprine HCl). 

Oxidation (H2O2) Degradation: 5.0 ml of SSS1, 5.0 ml of SSS2 & 5.0 ml of 3% H2O2 

solution were diluted to 50 ml with diluents. (Conc. 0.55 mg/ml paracetamol & 0.0055 

mg/ ml Cyclobenzaprine HCl). 

2.8 Stability of tabletx 

In this study, samples of mixed powder Cyclobenzaprine HCl & Paracetamol Tablets 

were paced in a high density polyethylene HDPE bottles covered with child proof caps, 

and stored at two different conditions at 25°C/60% RH & 40°C/75% RH. Testing 

Frequency: samples analyzed at different time intervals (Zero-time, 3
rd

 Month & 6
th 

month) in order to evaluate the changeover the time of the formula and its proper 

storage conditions. 

2.9 A pilot field study 

2.9.1 Study design and setting 

This study was a cross-sectional questionnaire-based to evaluate doctors’ and patients’ 

perspectives regarding the use of Paracetamol and Cyclobenzaprine HCl. It was 

conducted between March 2021 and December 2021. 

The population was doctors who may prescribe Cyclobenzaprine for patients in Nablus 

city. Convenience sampling was used to recruit participants. 

2.9.2 Inclusion and exclusion criteria 

The inclusion criteria were as follows for doctors: males and females, with specialties 

that may prescribe Paracetamol and Cyclobenzaprine as orthopedic doctors 

neurosurgeons and neurologists. The inclusion criteria for patients were male or female 

patients who were prescribed Cyclobenzaprine for any type of pain. 

 

 

 



21 

 

2.9.3 Data collection and management 

Data Collection Forms (Appendix B) were used to gather information. The form for 

doctors was in English and it included some sociodemographic data as gender, age, 

specialty, years of experience and working place, then they were asked about the 

frequency of prescribing these two medications and if they support combining them in a 

same tablet. For patients, the form was in Arabic and it included some 

sociodemographic data also as gender, age, education, living place, chronic disease, in 

addition to questions regarding the use of Paracetamol and Cyclobenzaprine. 

Initially the doctor prescribed Cyclobenzaprine HCl tablet as a muscle relaxant for the 

patient and asked him/her to use it for the first 3 days and record efficacy and any side 

effects then the doctor added Paracetamol tablet and tried to notice the differences 

before and after taking Paracetamol tablet. The doctor then completed the questionnaire 

for the patient.  

2.9.4 Ethical approval 

All aspects of the study protocol, including access to patients’ clinical information, were 

authorized by the Institutional Review Boards (IRBs) (Appendix C) before the initiation 

of this study. In addition, a verbal consent form was obtained from each patient 

(Appendix C). 

2.9.5 Statistical analysis  

The Statistical Package for Social Sciences program version 21 (SPSS) and Excel sheets 

were used to enter and analyze data. Data was expressed as mean ± SD for continuous 

variables and as frequencies (percentages) for categorical variables.  

 

 

 

 

 



20 

 

Chapter Three 

Results 

3. Results  

Solid dosage forms are the preferable ones among other pharmaceutical forms due to its 

stability, reproducibility, handling, and dosing. Successful formulation and evaluation 

of Cyclobenzaprine/paracetamol tablet will provide a new pharmaceutical combination 

with lower cost, which may improve the patient compliance by reducing the tablets 

needed to be taken and thus improve patient's compliance to prescribed therapeutics. 

3.1 Preformulation Testing 

3.1.1 Compatibility & flow properties 

For cyclobenzaprine bulk density was 0.48 g/ml, tapped density was 0.57 g/ml with 

compressibility index of 15.8 and Hausner Ratioof 1.17 and for Paracetamol bulk 

density was 0.43 g/ml, tapped density was 0.51 g/ml with compressibility index of 15.7 

and Hausner Ratio of 1.18 as index for flowability and compressibility of the 

formulated tablet. 

The powders results show good flowability properties with good compressibility index 

(11). 

3.1.2 Water Content/LOD Determination 
 

Table 1  

API& Excipients Water content (WC)/loss on drying (LOD) Results 

Material  Test Limit Result 

Cyclobenzaprine HCl LOD *NMT 5.0 % 0.9 % 

Paracetamol  LOD NMT 5.0 % 2.1 % 

Avicel 101 LOD NMT 7.0 % 4.8 % 

Magnesium stearate LOD NMT 6.0 % 2.7 % 

Sodium starch glucolate LOD NMT 10% 6.7 % 

*NMT: not more than 

LOD/W.C for each excipient should be within specifications, because out of range 

LOD/W.C results in stability problems and thus degradation of product. As illustrated in 

the table above all results are within specifications. 



22 

 

3.1.3 Excipients and APIs Compatibility 

Table 2 

Compatibility Testing Results. 

No (API: Excipient) Appearance Assay (API) 

after  month 

1 Paracetamol: Avicel 101 White powder 99.5% 

2 Paracetamol: magnesium stearate White powder 99.7 % 

3 Paracetamol: sodium starch glycolate White powder 99.2 % 

4 Paracetamol: Cyclobenzaprine HCl White powder 100.5%, 99.4% 

5 Cyclobenzaprine HCl: Avicel 101 White powder 100.0 % 

6 Cyclobenzaprine HCl: magnesium stearate White powder 99.5% 

7 Cyclobenzaprine HCl: sodium starch 

glycolate 

White powder 100.7% 

 

As obtained in the results above; no change in appearance of each mixture was observed 

after a month. In addition; no significant change in API Assay observed, which means 

that no impact of any used excipient on the quantitative and qualitative results of the 

API and more importantly the combing the two APIs is not expected to induce 

significant degradation of each.  

3.2 Preparation of the formulation (Optimized Formula) 

the optimized formula of the tablets was obtained as illustrated in Table 7. The powders 

were mixed using direct mixing and compressing method. 

All excipient was weighted and mixed well together, Paracetamol was added and mixed 

for 15 min then cyclobenzaprine was added and all powders mixed together for other 15 

min to ensure that the powders distributed well. Small amount of powder was taken for 

analysis and the other added to the hopper (inlet) of the compression machine and 

compressed to obtain a tablet with required specifications.  

 

 



23 

 

Table 3 

 Tablets Optimized Formula. 

No. Material Function Quantity 

(mg/tablet) 

(% w/w) 

I.  Paracetamol Active 500 76.9 

II.  Cyclobenzaprine HCl Active 5 0.769 

III.  Avicel 101 Binder 110 16.9 

IV.  sodium starch glycolate Disintegrant  10 1.54 

V.  magnesium stearate Lubricant  5 0.769 

Total Wt. of Tablet= 650 mg 

 

3.3 Evaluation of Compressed Tablets 

Description of Tablets  

The obtained tablets were oval convex tablet, white coloured free from spots, cleavage, 

cracking, and sticking.  

Accordingly the dimensions of Tablet, uniform dimensions (length and thickness) of 

tablets obtained after compression (Table 7), are evidence of good processing and good 

blend properties prior to compression including the optimized quantities of excipients 

used. (RSD between readings < 2.0 %). 

Table 4 

Tablets parameters (length, thickness & hardness). 

Tablet No. 
Parameter 

Length (mm) Thickness (mm) Hardness (Newton N) 

1 1.58 0.75 82 

2 1.58 0.75 76 

3 1.60 0.74 88 

4 1.59 0.75 79 

5 1.58 0.76 75 

6 1.57 0.76 79 

7 1.59 0.75 85 

8 1.58 0.75 81 

9 1.58 0.74 77 

10 1.59 0.74 86 

Average 1.58 cm 0.75 cm 82 N 

Specification 1.58 cm ±0.3 mm 0.75 cm ±0.3 mm Not less than (NLT) 60 

N 

SD 0.016364 0.021499 - 

RSD 0.15 % 0.5 % - 

 



24 

 

Friability and Disintegration Time 

Balance achieved between the three parameters (Disintegration Time & Friability) was 

acceptable for such dosage form leading to uncoated tablets that should be hard enough 

to be handled, disintegrate easily and meet friability criteria as shown in tables 8, 9 and 

10.  

Friability of tablets: 

The weight of tablets before test = 10 gm  

The weight after test = 9.982 gm 

The friability % = 0.18% which is in an acceptable limit (NMT 1.0%) 

Disintegration of the tablet: 

The disintegration results for 6 tablets were between 40 & 78 seconds with an average 

of 57 seconds which is in acceptable limit (NMT 15 min) 

Weight and Uniformity of Weight 

All tablets were uniform in weight with no deviation from the target weight by more 

than 5.0 %. This uniformity of weight also achieved by right selection of excipients 

quantities and processing method (Table 11). 

Table 5 

Weight Variation Results. 

Tablet No. Weight (mg) Tablet No. Weight (mg) 

1 658 11 659 

2 637 12 647 

3 662 13 662 

4 652 14 654 

5 645 15 637 

6 669 16 645 

7 637 17 660 

8 651 18 650 

9 659 19 658 

10 670 20 642 

Average weight = 652.7 mg 

SD= 1.5 

Minimum Wt. 617.5 mg 

Maximum Wt. 682.5 mg 

Acceptance Limit 650.0 mg ± 5.0 % 

 



25 

 

Dissolution/in vitro test 

Dissolution results were within acceptance limits, with low CV. This also a good 

indicator of uniform distribution of APIs within the blend before and during 

compression as well as good formulation that passed one of the critical quality attributes 

tests. 

Absorbance of Standard: 

Paracetamol Solution at 250 nm = 2.96 

Cyclobenzaprine HCl at 290 nm = 3.1 

Panadol tablet dissolution results: 

The mean of dissolution = 98.9%, the lower value was  97.5% and higher value was 

101.0%, which are within acceptable limit (NLT 70% Q) 

Xaprine tablet dissolution results: 

The mean of dissolution = 94.5%, the lower value was  92.5% and higher value was 

96.0%, which are within acceptable limit (NLT 70% Q). 

Formulated combined Paracetamol & Cyclobenzaprine HCl tablet dissolution 

results: 

For Paracetamol: The mean of dissolution = 101.5%, the lower value was  100.3% and 

higher value was 103.0%, which are within acceptable limit (NLT 70% Q). 

For Cyclobenzaprine: The mean of dissolution = 88.2%, the lower value was  97.1% 

and higher value was 89.7%, which are within acceptable limit (NLT 70% Q). 

Assay 

Percent (%) content of the API in the portion of powdered tablets taken for analyzing 

assay was high and within acceptance limit, with RSD less than 2.0 % between tested 

samples. The chromatographic trials and results were attached in appendix D. 

 

 

 



26 

 

Table 6 

Assay Results. 

Average paracetamol 

standard solution 

59922718 

Sample (1) %Assay= (61190065/59922718)×100= 102.1% 

Sample (2) %Assay= (60291303/59922718)×100= 100.6% 

Sample (3) %Assay= (60621468/59922718)×100= 101.2% 

Average Assay  101.3 % 

Acceptance Limit 90.0 %-110.0 % 

Average Cyclobenzaprine 

HCl standard solution 

1919711 

Sample (1) %Assay= (1885712/1919711)×100= 98.2% 

Sample (2) %Assay= (1918083/1919711)×100= 99.9% 

Sample (3) %Assay= (1976150/1919711)×100= 101.9% 

Average Assay  100.0% 

Acceptance Limit 90.0%-110.0 % 

 

3.4 Validation/Verification Results 

Any used analytical procedure for any test; should be validated /verified in order to 

assure that used procedure can achieve the desired purpose. This assessment can be 

judged according to several parameters to assure that the method is linear in the range 

used with high recovery and precision, good robustness and selectivity. 

Assay Validation 

Tables 14-17 and Figures 1 and 2 show validation results, which were all within the 

accepted range and the chromatographic results, were attached in appendix D. 

 

 

 

 

 



27 

 

I. Linearity and Range 

Table 7 

Assay Linearity Results for Paracetamol & Cyclobenzaprine HCl 

Pracetamol Conc. 

(mg/ml) 

Avg. Area of 

Paracetamol 

Cyclobenzaprine 

Conc. (mg/ml) 

Avg. Area of 

Cyclobenzaprine 

0.2 25307491 0.002 784484 

0.225 29478402 0.00225 893564 

0.25 32663902 0.0025 1005309 

0.275 34320554 0.00275 1050000 

0.3 38623912 0.003 1170930 

0.4 50934697 0.004 1539160 

0.45 56421714 0.0045 1724130 

0.5 62659004 0.005 1983586 

0.55 69021202 0.0055 2157754 

0.6 74102473 0.006 2316641 

R
2
 0.999 R

2
 0.9983 

Y-intercept  2*10
6 

Y-intercept  12985
 

Slope 1*10
8
 Slope 4*10

8
 

Acceptance Limit R
2
 NLT 0.98 Acceptance Limit R

2
 NLT 0.98 

 

‌  



28 

 

Figure 2 

Linearity of Assay for paracetamol. 

 
 

Figure 3 

Linearity of Assay for Cyclobenzaprine HCl. 

 

y = 1E+08x + 2E+06 
R² = 0.999 

0.0

10000000.0

20000000.0

30000000.0

40000000.0

50000000.0

60000000.0

70000000.0

80000000.0

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7

A
vg

 A
re

a 

Conc mg/ml 

Paracetamol 

y = 4E+08x + 12985 
R² = 0.9983 

0

500000

1000000

1500000

2000000

2500000

0 0.001 0.002 0.003 0.004 0.005 0.006 0.007

A
vg

 A
re

a 

Conc. mg/ml 

Cyclobenzaprine 



29 

 

As the above results illustrate; method of analyzing Assay is linear in the range of 0.2 

mg/ml to 0.6 mg/ml conc. for paracetamol and 0.002 mg/ml to 0.006 mg/ml for 

Cyclobenzaprine HCl. 

II. Precision 

Table 8 

Assay Precision Results. 

Sample No. Area of paracetamol (A.U) Area of Cyclobenzaprine HCl 

(A.U) 

1 62385309 1959491 

2 62621729 1943405 

3 62687558 1944042 

4 62481827 1952605 

5 62668664 1948029 

6 62739815 1943715 

Mean 62597484 1948548 

SD 135956.3 6427.912 

RSD 0.21% 0.33% 

Acceptance 

Limit 

RSD should not exceed 2.0 % 

 

As illustrated above; RSD between readings was 0.5 % < 2.0 %; which means that assay 

method is precise. 

  



31 

 

III. Accuracy and Recovery 

Table 9 

Assay Accuracy/Recovery Results for paracetamol. 

Conc. 

(mg/ml) 

Sample 

No. 

Area of 

Paracetamol 

(A.U) 

Area of 

Cyclobenzaprin

e HCl (A.U) 

% Recovery 

Paracetamol 

% Recovery 

Cyclobenzaprine 

HCl 

0.4 1 51094168 1503625 100.4 100.7 

0.4 2 50853868 1493975 100.0 100.0 

0.4 3 508976360 1494641 1000.5 100.1 

0.5 1 62866862 1962391 100.3 100.9 

0.5 2 62866862 1949041 100.3 100.3 

0.5 3 62725970 1946778 100.1 100.1 

0.6 1 73921612 2306714 99.7 100.8 

0.6 2 73902022 2292841 99.6 100.2 

0.6 3 73981606 2306714 99.8 100.8 

Acceptance Limit: Recovery should not exceed ± 2.0 % 
 

Recovery was within acceptance limit (±2 %) for every 3 samples analyzed at different 

concentrations from (80% to 120 % of target concentration). 

IV. Selectivity: no absorbance found for the placebo sample. 

V. Stability under stress conditions 

Stress conditions are necessary to develop a stability indicating method that illustrates 

all potential degradation products at different stressed conditions; without interfering 

with the API. This also helps in determining the suitable conditions for storage. The 

method shows a degradation result in the APIs when expressed under acidic, basic and 

oxidation condition. 

3.5 Stability Study Results 

Stability of formulated mixed powder tablets was studied after 3 and 6 months at 

different storage conditions (25 °C, 60 % RH) and at (40°C, 75% RH).  Stability results 

are listed in Table 18. As obtained from the results, the product was stable at the two 

different conditions; with slight changes at 40° Cover the time period; however, all 

results were within acceptable limits. 

 

 



30 

 

Table 10 

The result of stability listed in the following table 

Test for tablet Specification  3
rd 

Month result 6
th
 Month result 

25C/60%RH 40C/75%RH 25C/60%RH 40C/75%RH 

Length  1.58 cm ± 0.3 

mm 

1.57 mm 1.58 mm 1.59 mm 1.57 mm 

Thickness 0.75 cm ± 0.3 

mm 

0.76 mm 0.78 0.75 mm 0.74 mm 

Hardness  NLT 60 N  81  78 84 80 

Friability  NMT 1.0% 0.13% 0.16% 0.15% 0.18% 

Disintegration  NMT 15 min 1 min 52 sec 55 sec 57 sec 

Average weight  650.0 mg ± 5.0% 658.1 mg 656.1 mg 654.7 mg 654.0 mg 

Dissolution 

Paracetamol  NLT 70%Q 99.1% 98.5% N.A N.A 

Cyclobenzaprine 

HCl 

NLT 70%Q 90.7%  88.7% N.A N.A 

Assay  

Paracetamol  90.0%-110.0% 99.5% 99.3% 99.8% 98.5% 

Cyclobenzaprine 

HCl 

90.0%-110.0% 98.8% 98.1% 97.7% 98.0% 

 

  



32 

 

3.6 The pilot observation clinical study 

This part included two questionnaires:  

The doctor's questionnaires were answered by fifty doctors through a face-to-face 

interview (Figure 5). Around 50% of them were between 50 and 60 years old, 14.6% 

less than 30 years and 35.4% between 30 and 40 years, 64.6% were males. 18.8% had 

more than 20 years of experience, 12.5% had 10 to 20 years of experience, 18.8% had 

5-10 years of experience and 50% had less than 5 years of experience. Regarding their 

working places, 52.1% of doctors worked in governmental hospitals, 29.2% worked in 

private hospitals, 10.4% worked in private clinics, and 8.3% worked in other places. 

Their prescribing of Paracetamol was very common as 79.2% of them said that they 

prescribe it daily, while for cyclobenzaprine, the frequency of prescribing was divided 

as yearly, monthly, weekly, and daily (14.6%, 25.0%, 41.7%, and 18.8% respectively). 

Almost all doctors (93.8%) supported the idea of combining the two medications in one 

tablet and said it could be a tablet in tablet, mixed powder tablet, or two-layer tablet 

(29.2%, 39.6%, and 31.3%, respectively). 

The patient questionnaires were answered by thirty patients (Figure 6). The percentage 

of male patients was 57.1%, 92.9% were married, 50% were between 40 and 60 years 

old, 35.7% were less than 40 years old, and 14.3% were more than 60 years old, 32.1% 

had a university degree and 35.7% had only a high school, 39.3% had a monthly income 

of between 3000 and 5000 NIS, while for 36.7% it was between 1000 and 3000 NIS, 

10.7% of the patients had no health insurance, 46.4 had private health insurance and 

42.9% had government health insurance, 64.3% had no chronic diseases while 14.3% 

had diabetes and 10.7% had hypertension. Most of them evaluated their health status as 

excellent (71.4%). The reasons for visiting the doctor were back pain, neck pain, or 

others, with a percentage of 67.9%, 25.0%, and 7.1%, respectively. All were prescribed 

the trade name of Cyclobenzaprine HCl drug (Xaprine)® with a 5mg concentration. 

Only 10.7% of patients used Xaprine before this time. 14.3% of patients suffered from 

Xaprine side effects, which were tiredness, headache, dizziness, drowsiness, 

constipation, and dry mouth. All patients said that their symptoms improved when 

Paracetamol was added to Cyclobenzaprine. 

 



33 

 

The following figure (5,6) show the result: 

Figure 4 

Doctors’ questionnaire results (N =50) 

    

 

 
 

14.6 

50.0 

35.4 

Age 

50-60

<30

30-40

64.6 

35.4 

Gender 

Male Female



34 

 

 
 

 

 
 

18.8 

50.0 

18.8 

12.5 

Years of experience 

>20 <5

5-10. 10-20.

29.2 

52.1 

10.4 

8.3 

Working place 

Privet hospetal

Gover. Hospital

privit clinic

Other



35 

 

 
 

 
 
 
 

20.8 

79.2 

Paraetamol prescibtion frequincy 

Weekly Daily

14.6 

41.7 
18.8 

25.0 

Cyclobenzoprine prescrition frequancy 

Yearly

Weekly

Daily

Monthly



36 

 

 

 
 
 

 

 

 

 

93.75 

6.25 

The ideae is useful 

Yes

No

29.2 

39.6 

31.3 

Best formulation idea 

Tablet in tablet

Mixed powder

Two layer



37 

 

Figure 5 

Patients’ questionnaire results (N=30) 

 

 

 
 

57.1 

42.9 

Gender 

Male Female

92.9 

7.1 

Marital status 

Married

Single



38 

 

 

 

35.7 

50.0 

14.3 

Age 

<40

<60

>60

35.7 

32.1 

25.0 

7.1 

Education level 

High school University

Primary Higher than



39 

 

 

 

35.7 

39.3 

25.0 

Income level 

1000-3000

3000-5000

<5000

42.9 

46.4 

10.7 

Health insurance 

Govermental Private No



41 

 

10.7 

14.3 

64.3 

10.7 

Suffers from diseases 

Hypertension Diabetes

No diseases Othor

71.4 

25.0 

3.6 

Health status 

Excellent Very good

Good



40 

 

 

 

67.9 

25.0 

7.1 

Reason for visiting Dr. 

Pack pain Neck pain

Othor

100.0 

Drug trade name 

Xaprine



42 

 

 
 

 

 

 

 

100.0 

Cyclobenzaprine Conc. 

5 mg

10.7 

89.3 

Have you used Xaprine before this time? 

Yes

No



43 

 

Chapter Four 

Discussion and Conclusion 

4. Discussion and conclusion 

The effectiveness of Cyclobenzaprine is improved with paracetamol when they are 

taken together. Using a muscle relaxant and an analgesic is common for some types of 

muscle pain (28) . So a formulation of Cyclobenzaprine HCl and Paracetamol combined 

powder tablet was done to achieve an effective drug and reach consumer's requirements. 

Using both active ingredients in one tablet instead of using two separated tablets is 

easier for patients and may improve patient compliance. 

According to the results of the active pharmaceutical drug powder properties, bulk 

density, tapped density, compressibility index and Hausner ratio calculation were 

evaluated and the powder has good flowability properties with good compressibility 

(11). 

Active ingredients and excipients were within water content and loss of drying 

specification which have a good compatibility (14). The formulated tablet has 

disintegration time lower than 2 min. 

The direct compressed formulated tablet contained magnesium stearate as lubricant, 

sodium starch glycoside as disintegrant, avicel 101 as binder and Paracetamol 500mg 

and Cyclobenzaprine HCl 5mg as active ingredients.  

The formulated tablet is physically tested for colour, shape, length, thickness, hardness, 

weight, friability and disintegration. It was white in colour oval convex shaped 

compressed tablet that has a length of 1.58 cm ± 0.3 mm and 0.75 cm ± 0.3 mm in 

thickness, with an average of 82 N hardness and 652.7 mg weight, and acceptance result 

for friability and disintegration time test.  

The formulated tablet has a dissolution of NLT 70% Q and assay within the limit of 

90%-110%. And all these tests’ results were within the accepted and recommended 

ranges (14). 

 



44 

 

All tests under assay validation were within accepted limit also (16).This means that the 

method is linear with R
2 

more than 0.98, accurate with less than 2% recovery precise 

with %RSD less than 2%, and selective with no peak interference which means that it 

will give a good result on any HPLC by any expert analyst at a different  concentration 

and time (16). 

The formulated tablet was chemically and physically stable for 6 months at different 

storage zones (25 °C, 60 % RH) and at (40°C, 75% RH) (14).   

Regarding the questionnaires, they showed an acceptance for the combination of both 

drugs by the doctors and patients, the doctors told that they prescribe both medications 

together for muscle pain and almost all of them supported having the two active 

ingredients in one tablet. The patients were using the 5 mg dose of the cyclobenzaprine 

and all of them told that the efficacy of treatment improved when paracetamol was 

added which means that they also support having both medications together. 

4.1 Conclusion 

Cyclobenzaprine HCl and Paracetamol mixed powder tablets were successfully 

formulated and showed an acceptable stability profile. The developed and validated 

HPLC method was suitable for the characterization and assessment of the formulated 

tablets and can be used for convenient forms analysis especially for those tests not listed 

in the pharmacopeias. 

The formulated mixed powder compressed tablet can be manufactured in 

pharmaceutical companies with a stable formula physically and chemically and 

validated test method.  

The future work may concentrate on changing the type of formulated tablet as many 

layer tablet, tablet in tablet or other types, or may try to work on adding other active 

ingredients to have more effective tablets, in addition to having different strength of 

both medications, such as adding caffeine which may potentiate the analgesic effect of 

paracetamol and at the same time lessen the sedative side effect of cyclobenzaprine. 

 

 



45 

 

List of Abbreviations 

Meaning Abbreviation 

Active ingredients  APIs 

Celsius grade ºC 

Central nervous system CNS 

Corrective value  CV 

Critical quality attributes CQA 

Gastro intestinal  GI 

Gram g 

High density poly ethylene HDPE 

High performance liquid chromatography HPLC 

Hour hr 

Liquid chromatography LC 

Maximum concentration Cmax 

Maximum time  Tmax 

Micro liter µL 

Micro meter µm 

Microgram  µg 

Milligram mg 

Milliliter  ml 

Millimeter mm 

Minutes min 

Nano gram ng 

Nanometer  nm 

Newton N 

Not less than NLT 

Not more than NMT 

Over the counter OTC 

Quality by design QbD 

Quality target product profile QTPP 

Reference listed drug  RLD 

Relative humidity RH 



46 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Relative standard deviation RSD 

Revolution per minutes rpm 

Second Sec 

Ultra violet UV 

United states food and drug administration U.S. FDA 

Volumetric flask VF 

World health organization WHO 



47 

 

References 

[1] United States Pharmacopeia and National Formulary (USP 39-NF 34): United 

States Pharmacopeial Convention; 2018. 1445 p. 

[2] Shah B, Gibson J, Tex N. Dosage Forms, Routes of Administration, and 

Dispensing Medications.  The 21st Century Pharmacy Technician. 1 ed: Jones & 

Bartlett Learning, LLC; 2013. p. 80-110. 

[3] Qumseya BJ, Tayem YI, Dasa OY, Nahhal KW, Abu–Limon IM, Hmidat AM, et 

al. Barriers to colorectal cancer screening in Palestine: A national study in a 

medically underserved population. Clinical Gastroenterology and Hepatology. 

2014;12(3):463-9. 

[4] Augsburger LL, Hoag SW. Pharmaceutical Dosage Forms. 1st ed. London: 

Taylor& Francis Group; 2017. 

[5] Lieberman HA, Lachman L, Schwartz JB. Pharmaceutical dosage forms--

tablets/edited by Herbert A. Lieberman, Leon Lachman, Joseph B. Schwartz. 

1989. 

[6] Pharmacopeial-Forum. General Chapter <1151> Pharmaceutical Dosage Forms: 

The United States Pharmacopeial Convention; 2009. 

[7] Revision of monograph on tablets.  The International Pharmacompeia World 

Health Organization; 2011. 

[8] Chen Y, Feng T, Li Y, Du B, Weng W. Formulation and evaluation of a 

montelukast sodium orally disintegrating tablet with a similar dissolution profile 

as the marketed product. Pharmaceutical development and technology. 

2017;22(2):168-72. 

[9] Kumar M, Bhatia R, Rawal RK. Applications of various analytical techniques in 

quality control of pharmaceutical excipients. Journal of pharmaceutical and 

biomedical analysis. 2018;157:122-36. 

[10] Sinka I, Motazedian F, Cocks A, Pitt K. The effect of processing parameters on 

pharmaceutical tablet properties. Powder Technology. 2009;189(2):276-84. 

[11] Gibson M. Pharmaceutical Preformulation and Formulation. 2 ed. Gibson M, 

editor. USA: Informa Healthcare; 2009. 



48 

 

[12] Quality by Design for ANDAs: An Example for Immediate-Release Dosage 

Forms. Food and Drug Administration, 2012. 

[13] Swartz ME, Krull IS. Analytical Method Development and Validation. 1 ed: CRC 

Press; 1997. 96 p. 

[14] Guidance for Industry: Q8 (R2) Pharmaceutical Development. USA: US Food and 

Drug Administration Center for Drug Evaluation and Research; 2009. 

[15] Rignall A. ICHQ1A (R2) stability testing of new drug substance and product and 

ICHQ1C stability testing of new dosage forms. ICH Quality Guidelines: An 

Implementation Guide. 2017;3. 

[16] ICH. Validation of Analytical Procedures: Text and Methodology: EMEA; 2006. 

[17] USP40-NF35. Validation of Compendial Procedures: United States 

Pharmacopeial Convention; 2018. 1780 p. 

[18] Venkataraman S, Manasa M. Forced degradation studies: Regulatory guidance, 

characterization of drugs, and their degradation products-a review. Drug Invention 

Today. 2018;10(2). 

[19] Ngwa G. Forced degradation as an integral part of HPLC stability-indicating 

method development. Drug delivery technology. 2010;10(5):56-9. 

[20] Kaufman DR, Pevzner J, Hilliman C, Weinstock RS, Teresi J, Shea S, et al. 

Redesigning a telehealth diabetes management program for a digital divide 

seniors population. Home Health Care Management & Practice. 2006;18(3):223-

34. 

[21] Toth PP, Urtis J. Commonly used muscle relaxant therapies for acute low back 

pain: a review of carisoprodol, cyclobenzaprine hydrochloride, and metaxalone. 

Clinical therapeutics. 2004;26(9):1355-67. 

[22] Katz WA, Dube J. Cyclobenzaprine in the treatment of acute muscle spasm: 

review of a decade of clinical experience. Clinical therapeutics. 1988;10(2):     

216-28. 

[23] Chou R, Peterson K, Helfand M. Comparative efficacy and safety of skeletal 

muscle relaxants for spasticity and musculoskeletal conditions: a systematic 

review. Journal of pain and symptom management. 2004;28(2):140-75. 



49 

 

[24] van Tulder MW, Touray T, Furlan AD, Solway S, Bouter LM. Muscle relaxants 

for non‐specific low‐back pain. Cochrane database of systematic reviews. 

2003(2). 

[25] Medicine NLo. Cyclobenzaprine American Society of Health-System 

Pharmacists, Inc. Disclaimer: American Society of Health-System Pharmacists, 

Inc. Disclaimer; 2017 [cited 2022 15 02 2022]. Available from: 

https://medlineplus.gov/druginfo/meds/a682514.html  

[26] (2022). NCfBI. . PubChem Compound Summary for CID 1983, Acetaminophen 

PubChem [Internet]. Bethesda (MD): : National Library of Medicine (US),; 1983 

[cited 2022]. Available from: 

https://pubchem.ncbi.nlm.nih.gov/compound/Acetaminophen. 

[27] Kobayashi H, Hasegawa Y, Ono H. Cyclobenzaprine, a centrally acting muscle 

relaxant, acts on descending serotonergic systems. European Journal of 

Pharmacology. 1996;311(1):29-35. 

[28] . NCfBI. PubChem Compound Summary for CID 2895, Cyclobenzaprine 2004 

[cited 2022 Retrieved June 28, 2022 ]. Available from: 

https://pubchem.ncbi.nlm.nih.gov/compound/Cyclobenzaprine. 

 

 

 

 

 

 

 

 

 

 

 



51 

 

Appendices 

Appendix A 

Tables of Study 

Table A.1 

General stability storage conditions 

Study Term Storage Condition 
Minimum Period of 

Study at Submission 

Long term 

25°C± 2°C/60% RH± 5% RH 

or: 

30°C± 2°C/65% RH± 5% RH 

12 Months 

Intermediate  
30°C± 2°C/65% RH± 5% RH 6 Months 

Accelerated 45°C± 2°C/75% RH± 5% RH 6 Months 

 

Table A.2 

Scale of Flowability 

Compressibility Index Powder Flow Properties Hausner Ratio 

≤ 10 Excellent 1.00-1.11 

11-15 Good 1.12-1.18 

16-20 Fair 1.19-1.25 

21-25 Passable 1.26-1.34 

26-31 Poor 1.35-1.45 

32-37 Very Poor 1.46-1.59 

>38 Very. Very Poor >1.60 

 

Table A.3 

API& Excipients Water content (WC)/loss on drying (LOD)  

Material  Test Limit 

Cyclobenzaprine HCl LOD *NMT 5.0 % 

Paracetamol  LOD NMT 5.0 % 

Avicel 101 LOD NMT 7.0 % 

Magnesium stearate LOD NMT 6.0 % 

Sodium starch glucolate LOD NMT 10% 

*NMT: Not more than. 

 

 



50 

 

Table A.4 

(API: Excipients) Ratios for Compatibility Test. 

No. (API: Excipient) Ratio 

1 Paracetamol: Avicel 101 (1:1) 

2 Paracetamol: magnesium stearate (1:1) 

3 Paracetamol: sodium starch glycolate (1:1) 

4 Paracetamol: Cyclobenzaprine HCl (1:1) 

5 Cyclobenzaprine HCl: Avicel 101 (1:1) 

6 Cyclobenzaprine HCl: magnesium stearate (1:1) 

7 Cyclobenzaprine HCl: sodium starch glycolate (1:1) 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 



52 

 

Appendix B 

Data collection form 

 اسرًارج‌تحث‌عهًي

 

  

 

 

 

 

 انُجاح‌انٕطُيح‌جايعح

 

 كهيح‌انذراساخ‌انعهيا

 ياجسرير‌عهٕو‌صيذالَيح

 

 اسرًارج‌رقى‌)‌‌‌(

 

 

 

 

 

 

2022/2021 

 



53 

 

ىحا االستبيان تقؾم بو طالبة ماجدتيخ عمؾم صيجالنية في جامعة الشجاح الؾطشية لغخض الجراسة العمسية لتقييؼ 

دواء مخخى العزالت مع السدكؽ وىسا سيكمؾبيشدوبخابؽ مع الباراسيتامؾل الفعالية واألعخاض الجانبية الشاتجة عؽ 

 لجى السخضى في فمدظيؽ.

 نخجؾ االجابة عمى جسيع األسئمة بجقة عمسا بأنيا ستدتخجم ألغخاض البحث العمسي.

 

 

 _____________________ العمر:  ✔

   أنث      ذكر   الجنس:  ✔

✔  :  أعىل من ذلك التعليم الجامع  المرحلة الثانوي     المرحلة االبتدائية/اإلعدادية      أمي  المستوى التعليمي

؟ ✔ ن ي فلسطي 
ن
 مخيم   قرية   مدينة  أين تعيش ف

وج    أعزب   الحالة االجتماعية:  ✔ ن   أرمل   مطلق  مت 

 0111أكت  من    1000-3000     0111-0111   0111اقل من الدخل الشهري للعائلة بالشيكل:  ✔

؟ ✔ ن صحي  حكومي   هل لديك تأمي 
ن ن خاص   نعم, تأمي   ال   نعم, تأمي 

 سيئة   مقبولة   جيدة  جيدة جدا        ممتازة  الحالية الصحية بشكل عام:  ✔

 

 

 

 

 

 

 

 

 

 

 

 

 

يعهٕياخ‌عايحاألٔل‌:‌انقسى‌  
 



54 

 

 

 

 سثة‌انحضٕر‌نهطثية‌:‌

 االيراض‌انري‌ذعاَي‌يُٓا‌:‌

 ْم‌ذسرعًم‌ادٔيح‌اخرٖ‌يرخيح‌نهعضالخ‌أ‌دٔاء‌اخر‌يع‌انسيكهٕتيُزٔتريٍ‌:‌‌‌‌‌‌‌‌‌‌‌ال‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌َعى‌‌

 )في‌حال‌انجٕاب‌ب‌َعى(‌يا‌ْي‌االدٔيح‌االخرٖ‌:‌

Medication No.  

  

  

  

  

  

  

  

 

 5‌mg                 10 mgجرعح‌انذٔاء‌:‌‌‌‌‌‌‌‌‌‌‌‌‌

 االسى‌انرجاري:

 ْم‌اسرعًهد‌سايكهٕتُزٔترايٍ‌يٍ‌قثم:‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌َعى‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌ال

 ْم‌فعانيح‌انذٔاء‌كاَد‌افضم‌خالل‌اسرخذايّ‌يع‌انثاراسيرايٕل:‌:‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌َعى‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌ال

 

 

 

 

 

 

 

 

يانقسى‌انثاَي‌:‌انراريخ‌انًرض  

 



55 

 

 

 

 ْم‌عاَيد‌يٍ‌اي‌يٍ‌االعراض‌انرانيح‌تعذ‌اسرعًال‌دٔاء‌سايكهٕتُزٔترايٍ:

 ال َعى االعراض‌انجاَثيح

   انُعاس

   انرعة

   ٔجع‌في‌انراس

   دٔخح

   جفاف‌تانفى

   االو‌في‌انًعذج‌

   غثياٌ

   ايساك

 

انثراسيرايٕل‌ْم‌االعراض‌/تعضٓا‌انري‌عاَيد‌يُٓا‌يٍ‌انسيكهٕتُزٔتراٌ‌ٔحذِ‌عُذ‌ذُأل‌انسيكهٕتُزٔترايٍ‌يع‌

 قهد‌أ‌اخرفد:‌‌‌‌‌‌‌‌‌َعى‌‌‌‌‌‌‌‌‌‌‌‌ال

 :  اذا كان الجواب نعم , ما هي

 

 شكرا‌نرعأَكى

 

 

 

 

 

 

 

 

األعراض‌انجاَثيح‌يٍ‌انذٔاء‌انقسى‌انثانث‌:  
 



56 

 

Data Collection Form 

Dear doctor, could you please give us a few minutes to fill this questionnaire.  

We are carrying out this questionnaire as a part of master thesis to study a muscle relaxant drug 

(Cyclobenzaprine HCl) in term of uses and whether it is used with Paracetamol, how often they 

are both prescribed together and to collect opinions about development of a new formulation 

that contains both drugs in one tablet to meet patient compliance.  

 

Sociodemographic data 
 

Gender 

• Male   

• Female 

 

Age 

• < 30 years 

• 30-40 years 

• 50-60 years 

• >60 years 

 

Place of work 

• Governmental hospital 

• Private hospital 

• Governmental healthcare center 

• Private clinic 

• Others: ________________________ 

 

Specialty:  

• Orthopedics doctor, if you have subspecialty, please identify _____________________ 

• Surgical, if you have subspecialty, please identify _____________________ 

• Nerve doctor, if you have subspecialty, please identify _____________________ 

• Others: _________________ 

 

Years of experience” 

• < 5 years 

• 5-10 years 

• 10-20 years 

• >20 years 

 



57 

 

Paracetamol is a commonly used analgesic. How often do you prescribe paracetamol 

(acetaminophen)?  

• Daily 

• Weekly 

• Monthly 

• Yearly 

 

Cyclobenzoprine is a muscle relaxant. How often do you prescribe Cyclobenzoprine?  

• Daily 

• Weekly 

• Monthly 

• Yearly 

 

Do you need sometimes to  prescribe Paracetamol with Cyclobenzoprine?          

• Yes 

• No 

If yes, In what cases both drugs may be prescribed togather for the same patient? 

……………………………………………………………………………………………………

……………………………………………………………………………………………………

……………………………………………………………………………………………………

……… 

 

In your opinion Is it a useful idea to develop Cyclobenzaprine HCl and paracetamol in a 

combination as a one tablet drug? 

• Yes   

• No 

 

If yes, what do you think the best formulation type is: 

• Mixed powder tablet. 

• Two layer tablet. 

• Tablet within tablet. 

 

Other notes: 

……………………………………………………………………………………………………

……………………………………………………………………………………………………

……………………………………………………………………………………………………

……… 

We thank you for your cooperation 

 

 

 



58 

 

Appendix C 

IRB approval 

 

 

 

 

 



59 

 

Appendix D 

Chromatogram results 

Trials 

 

 



61 

 

 



60 

 



62 

 



63 

 

Validation chromatograms:



64 

 



65 

 



66 

 

 



67 

 



68 

 



69 

 



71 

 



70 

 



72 

 



73 

 



74 

 



75 

 

 



76 

 



77 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 



 

 

 

 

 

 

 

 جــــامعــــــــة النجاح الهطنية
 كميـــــة الدراســــــــات العميــــــا

  

 

 

 

 

تصميم وتركيب وتطهير طريقة التحميل لمنتج حبهب 

والباراسيتامهلين االدايكمهبينزابر   

 

 ِإعداد
 رغد عبد الرؤوف صبحي لبادة

 
 إشراف

د. عبد الناصر زيد أ.  
د. رواء الرمحي أ.  

 
 

من كمية الدراسات  ،قدمت ىذه الرسالة استكماال لمتطمبات الحصهل عمى درجو الماجدتير في العمهم الصيدالنية
 فمدطين. -العميا، في جامعة النجاح الهطنية، نابمس

 

2022 



 ب‌

 

 ين والباراسيتامهلاتصميم وتركيب وتطهير طريقة التحميل لمنتج حبهب الدايكمهبينزابر 

 اعداد
 رغد عبد الرؤوف صبحي لبادة

 إشراف
 أ.د. عبد الناصر زيد
 أ.د. رواء الرمحي

 الممخص

الديكمؾبشدابخيؽ والباراسيتامؾل مؽ األدوية التي قج تحتاج إلى تشاوليا مًعا، يدتخجم  الخمفية:

 الديكمؾبيشدابخيؽ ىيجروكمؾرايج كسخخي لمعزالت والباراسيتامؾل كجواء لتدكيؽ اآلالم.

: كان اليجف مؽ ىحه الجراسة ىؾ ترشيع وتقييؼ ثبات حبؾب الديكمؾبشدابخيؽ والباراسيتامؾل عشج اليدف

لتحقق مؽ ترشيعيا في حبؾب تحتؾي عمييسا مًعا. باإلضافة إلى ذلػ ، تؼ تظؾيخ طخيقة فحص ججيجة تؼ ا

 الختبار جؾدة وثبات الحبؾب التي تؼ ترشيعيا. HPLCصحتيا بالكامل واستقخارىا وىي طخيقة تحميل 

: تؼ تحديؽ صيغة حبؾب تحتؾي عمى الديكمؾبشدابخيؽ والباراسيتامؾل كالىسا معا واختياره وفًقا لعجة الطريقة

يخ األقخاص السخغؾبة التي يجب ( لتظؾ QbDمعاييخ؛ تؼ استخجام بعض عشاصخ الجؾدة حدب الترسيؼ )

د حؾل عؾامل الجؾدة الشؾعية التي قج تتأثخ  أن تكؾن فعالة عالجيًا. وبشاًء عمى ذلػ، تؼ إجخاء بحث مخكَّ

بتغييخ واقعي في صياغة السشتج الجوائي أو عسمية الترشيع أثشاء التظؾيخ الريجالني. وتزسشت قياس 

ان وفحص التحمل. عالوة عمى ذلػ؛ تؼ تقييؼ ثبات األقخاص بعج ندبة السادة الفعالة في السدتحزخ والحوب

والتحقق مؽ صحتيا وفًقا  HPLCأشيخ في عل عخوف تخديؽ مختمفة. تؼ تظؾيخ طخيقة التحميل  6و  3

 لمستظمبات الخاصة.



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مؾحجة  ممغ باراسيتامؾل 555ممغ مؽ سيكمؾبشدابخيؽ و 5الشتائج: كانت حبؾب خميط البؾدرة السكؾنة مؽ 

ممغ، ىي أقخاص محجبة بيزاوية الذكل مع عجم وجؾد عيؾب في الذكل بعج  655الؾزن بستؾسط 

السعالجة أو تغيخات في قظخىا أو سسكيا. كانت جسيع معاييخ جؾدة السشتج ضسؽ السؾاصفات بسا في ذلػ 

 تمػ الخاصة بدسات الجؾدة الحخجة وغيخ الحخجة.

تؼ إجخاء طخق التحقق الكاممة مؽ الرحة والثبات لإلجخاءات التحميمية السدتخجمة في اختبار ندبة السادة 

Rالفعالة وندبة التحمل، حيث أعيخت الظخق السدتخجمة في التحميل ذوباًنا خظًيا عالًيا مع دقة 
أكثخ مؽ  2

٪ جسيعيا لـمديكمؾبشدابخيؽ 052-5..0٪ ونتائج الجقة بيؽ 2مع انحخاف معياري ندبي أقل مؽ  5.00

 والباراسيتامؾل.

لؼ يغيخ ثبات أقخاص البؾدرة السحزخة أي تغيخات في جسيع الستغيخات السختبخة؛ التي كانت ضسؽ الحجود 

أشيخ(. لحلػ يسكؽ ترشيع حبؾب  اـمديكمؾبشدابخيؽ والباراسيتامؾل  6السقبؾلة خالل فتخة الثبات السختبخة )

ة واحجة والتي ستكؾن عمى شكل جخعات ذات معاييخ جؾدة جيجة؛ وىحا مشاسب كخميط مع بعزيا في حب

 إلرخاء العزالت وتدكيؽ اآلالم معا.

: تست ترشيع حبؾب اـمديكمؾبشدابخيؽ والباراسيتامؾل كحبة واحجة معا بشجاح وأعيخت نتائج ثباتية الخالصة

شاسبة لتؾصيف وتقييؼ الحبؾب التي تؼ تظؾيخىا والتحقق مؽ صحتيا م HPLCمقبؾلة. كانت طخيقة 

السرسسة ويسكؽ استخجاميا لتحميل تمػ الحبؾب حيث ان االختبارات غيخ مجرجة في السخاجع الخاصة 

 لالدوية.

 : سيكمؾبشدابخيؽ، باراسيتامؾل، ترشيع، تثبت، حبؾب.الكممات المفتاحية