Angle of Repose

(1)

FORMULATION AND EVALUATION OF ORALLY DISINTEGRATING MINI TABLETS OF CEFPROZIL FOR PAEDIATRIC USE FOR THE

TREATMENT OF UPPER RESPIRATORY TRACT INFECTIONS

A Dissertation submitted to

THE TAMIL NADU Dr. M.G.R MEDICAL UNIVERSITY CHENNAI – 600 032

in partial fulfillment of the requirements for the award of degree of MASTER OF PHARMACY

IN

PHARMACEUTICS

Submitted by G.REKA

Reg. No. 261711257

Under the guidance of

Prof. K. Elango, M. Pharm., (Ph.D.) Professor and Head

Department of Pharmaceutics

COLLEGE OF PHARMACY MADRAS MEDICAL COLLEGE

CHENNAI – 600 003 MAY – 2019

(2)

DEPARTMENT OF PHARMACEUTICS COLLEGE OF PHARMACY MADRAS MEDICAL COLLEGE

CHENNAI-600 003 TAMILNADU

DATE: / / 2019

CERTIFICATE

This is to certify that the dissertation entitled “FORMULATION AND EVALUATION OF ORALLY DISINTEGRATING MINI TABLETS OF CEFPROZIL FOR PAEDIATRIC USE FOR THE TREATMENT OF UPPER RESPIRATORY TRACT INFECTIONS” submitted by G.REKA with Reg. No.

261711257 to The Tamil Nadu Dr. M.G.R. Medical University examination is evaluated.

1.

2.

(3)

COLLEGE OF PHARMACY MADRAS MEDICAL COLLEGE

CERTIFICATE

261711257 in partial fulfillment of the requirements for the award of the degree of MASTER OF PHARMACY in PHARMACEUTICS by The Tamil Nadu Dr.

M.G.R. Medical University is a bonafide work done by her during the academic year 2018-2019.

Place: Chennai-03 Date:

(Dr. A. JERAD SURESH, M. Pharm., Ph.D., M.B.A)

(4)

DEPARTMENT OF PHARMACEUTICS COLLEGE OF PHARMACY MADRAS MEDICAL COLLEGE

CERTIFICATE

261711257 in partial fulfillment of the requirements for the award of the degree of MASTER OF PHARMACY in PHARMACEUTICS by The Tamil Nadu Dr.

M.G.R. Medical University is a bonafide work done by her during the academic year 2018-2019 under my guidance.

Place: Chennai-03 Date:

[Prof. K. ELANGO, M. Pharm., (Ph.D.)]

(5)

ACKNOWLEDGEMENT

I take this privilege and pleasure to acknowledge the contributions of many individuals who have been inspirational and supportive throughout my work. It is not a chronology of events, but a collection of ideas at work, therefore this is the time to say sincere thanks to all those who have, in someway or the other helped me to sail through.

I acknowledge my sincere thanks to Dr. A. Jerad Suresh, M.Pharm., Ph.D., MBA, Principal, College of Pharmacy, Madras Medical College, Chennai, for his continuous support in carrying out our project work in this institution.

I take this opportunity and it gives me immense pleasure to express my deep sense of gratitude to my Professor K.Elango, M.Pharm., (Ph.D.), Professor and Head. Department of Pharmaceutics, College of Pharmacy, Madras Medical College, Chennai-03 for his continuous guidance, supportive suggestions, innovative ideas which made me to do my thesis the best.

`I am thankful to all of my teaching staff member Mr. K. Ramesh Kumar, M.Pharm.,(Ph.D), Dr.S.Daisy Chellakumari, M.Pharm., Ph.D., Dr.N.Deattu, M.Pharm., Ph.D., and Dr. R. Devi Damayanthi, M.Pharm.,Ph.D. of the Department of Pharmaceutics, College of Pharmacy, Madras Medical College, Chennai for their valuable suggestions, constant support and encouragement.

It’s a great pleasure to acknowledge my sincere thanks to Dr.P.Sunitha, M.Pharm, Ph.D., for her FTIR spectral interpretation of my project work.

I extend my thanks to all non-teaching staff members Mrs.Kumuthavalli, Mr.Sayapathy Department of Pharmaceutics, College of Pharmacy, Madras Medical College, Chennai.

I would express my sincere thanks to Mr Mahendran, B.Pharm Mr. Suyaraj, Mr.K. Narendra B.Pharm and Ms. P.Vijyalakshmi of M/s. Kaushik Therapeutics Private Ltd, Chennai and Mr. G.Ramesh Kuma, B.Pharm of M/s. SGS Formulations, Chennai.

for their supporting on this project work.

I would like to express my sincere thanks to my friends P.Prasath, K.P.Rama, who stood beside me throughout my project.

(6)

I extend my cordial thanks to all my Seniors and Juniors for their kind support and made a fun filled environment throughout the course of study.

I would like to thank, Government of India for granting me the No objection certificate to study M. Pharm. during my service.

I would like to express my special gratitude to my beloved family, father, mother, siblings for their support and encouragement. Finally, I am very grateful to my lovely husband and soul mate for him love, support and encouragement. Thank you for being patient during my graduate studies.

I dedicate this whole dissertation to my husband.

(7)

ABBREVIATIONS AND SYMBOLS

API Active Pharmaceutical Ingredients AOM Acute Otitis Media

AS Acute Sinusitis’s

BCS Biopharmaceutical Classification System BP British Pharmacopoeia

CFU/ml Colony-forming units per milliliter CCS Croscarmellose Sodium

CPZ Cefprozil

Cum Cumulative

DC Direct Compression

DMT Dispersible Mini Tablets EMA European Medicines Agency

e.g Example

Etc Et cetra

FT - IR Fourier Transform Infra Red GRAS Generally Regarded As Safe

ICH International Conference on Harmonization IP Indian Pharmacopoeia

IR Infra Red

JP Japanese Pharmacopoeia

KBr Potassium Bromide

MCC Microcrystalline Cellulose

Min. Minutes

Mg Milligram

Ml Millilitre

µg Microgram

ODMTs Orally Disintegrating Mini Tablets OME Otitis media with effusion

OM Otitis media

Pk Pharmacokinetics

PD Pharmacodynamics

Ph.Eur European pharmacopoeia

RH Relative Humidity

rOM recurrent otitis media RPM Revolution Per Minute SSG Sodium Starch Glycolate SSF Sodium Stearyl Fumarate SWT Simulated Wetting time

Sec. Seconds

S.D Standard Deviation

URTI Upper Respiratory Tract Infection

UV Ultra Viloet

USP United States Pharmacopoeia

° Degree

° C Degree Celsius

% Percentage

(8)

LIST OF TABLES TABLE.

No TITLE PAGE

No 1. Properties of multi unit and single unit dosage forms

8 2. Classification of Super disintegrant 17 3. Example of Commercially Available Mini-tab

Products in USA 18

4.

Comparison of signs and symptoms in adults and

children 34

5.

The list of drug and excipients, their manufacturer and

role in the present study 60

6.

Equipment’s used in the formulation and evaluation of

Mini tablets 61

7.

Angle of Repose, Compressibility Index and

Hausner’s ratio 65

8.

Composition of Cefprozil orally disintegrating Mini

tablets 66

9. Weight Variation

68 10.

Diffusion exponent and solute release mechanism for

cylindrical shape 72

11. Melting Point of Cefprozil Monohydrate

73 12. Drug – Excipients Physical compatibility studies

74 13. IR Spectral interpretation of Cefprozil Monohydrate 76 14. IR of Cefprozil Monohydrate with SSG

77 15. IR of Cefprozil Monohydrate with CCS

78 16. IR of Cefprozil Monohydrate with MCC

79 17. IR of Cefprozil Monohydrate with MS

80 18. IR of Cefprozil Monohydrate with Aspartame

81 19. IR of Cefprozil Monohydrate with Aerosil

82 20. IR of Cefprozil Monohydrate with Mannitol

83

(9)

21. Data of calibration curve Cefprozil Monohydrate 84 22.

Bulk density of Cefprozil Monohydrate and CPZ

blend 85

23.

Tapped density of Cefprozil Monohydrate and CPZ

blend 86

24. Compressibility Index of Cefprozil Monohydrate and

CPZ blend 87

25.

Hausner’s Ratio of Cefprozil Monohydrate and CPZ

blend 88

26.

Angle of Repose of Cefprozil Monohydrate and CPZ

blend without glidant 89

27.

Angle of Repose of Cefprozil Monohydrate blend with

glidant 90

28.

Diameter and Thickness of the formulated Cefprozil

ODMTs 91

29. Hardness of the formulated Cefprozil ODMTs

93 30. Weight variation of the formulated Cefprozil ODMTs

94 31. Friability of the formulated Cefprozil ODMTs

95 32.

Disintegration time of the formulated Cefprozil

ODMTs 96

33. Drug Content of the formulated Cefprozil ODMTs

97 34.

In vitro drug release study of Cefprozil orally

disintegrating Mini tablet Formulations. 98

35.

In-vitro Release Kinetics of Cefprozil Dispersible

Mini Tablets 100

36. R²values of various kinetic models

103 37. Content Uniformity of the Cefprozil ODMTs (F3)

104 38. Physical parameter results of the Cefprozil ODMTs

(F3) 105

39. In vitro drug release study of the Cefprozil ODMTs

(F3) -Stability studies 105

(10)

LIST OF FIGURES FIGURE.

No.

TITLE PAGE

No.

1. Mini tablets and their packaging configurations 9

2. Tableting methods 13

3. Mini tablets tools 13

4. Types of staples used in mini tablet production 13

5. Flowchart for Plan of Work 26

6. Upper respiratory system 31

7. Natural history and symptoms of rhinovirus infection

34 8. Flowchart for formulation of orally disintegrating

Mini tablets of Cefprozil

67 9. Spectrum of Cefprozil Mono hydrate

73 10. FT-IR spectra of Cefprozil Monohydrate 76 11. FT-IR spectra of Cefprozil Monohydrate with SSG 77 12. FT-IR spectra of Cefprozil Monohydrate with CCS 78 13. FT-IR spectra of Cefprozil Monohydrate with

MCC

79 14. FT-IR spectra of Cefprozil Monohydrate with MS 80 15. FT-IR spectra of Cefprozil Monohydrate with

Aspartame

81 16. FT-IR spectra of Cefprozil Monohydrate with

Aerosil

82 17. FT-IR spectra of Cefprozil Monohydrate with

Mannitol

83 18. Calibration curve of Cefprozil monohydrate 84

(11)

19. Bulk density 85

20. Tapped density 86

21. Compressibility Index 87

22. Hausner’s Ratio 88

23. Angle of Repose with out Glidant 89

24. Angle of Repose with Glidant 90

25. Diameter of Cefprozil ODMTs 92

26. Thickness of Cefprozil ODMTs 92

27. Hardness of Cefprozil ODMTs 93

28. Weight variation of ODMTs 94

29. Friability of Cefprozil ODMTs 95

30. Disintegration time of Cefprozil ODMTs 96

31. Drug Content of Cefprozil ODMTs 97

32. In-vitro drug release of Cefprozil ODMTs 99

33. Zero order kinetics 100

34. First order kinetics 101

35. Higuchi kinetics 101

36. Hixson Crowell Cube Root Kinetics 102

37. Korsmeyer Peppas kinetics 102

(12)

TABLE OF CONTENTS

CHAPTER CONTENTS PAGE NO

1 INTRODUCTION 1-18

2 REVIEW OF LITERATURE 19-24

3 AIM AND OBJECTIVE 25-27

4 RATIONALE OF STUDY 28-29

5 DISEASE PROFILE 30-38

6 DRUG PROFILE 39-44

7 EXCIPIENTS PROFILE 45-59

8 MATERIALS AND METHODS 60-72

9 RESULTS AND DISCUSSION 73-105

10 SUMMARY AND CONCLUSION 106-107

11 BIBLIOGRAPHY 108-113

(13)

1. INTRODUCTION

Department of Pharmaceutics, COP, MMC, Chennai -03. Page 1

1.1. ORAL DRUG DELIVERY SYSTEM ^{1, 2}

There are numerous dosage forms into which a drug substance can be incorporated for the convenient and efficacious treatment of a disease. Dosage forms can be designed for administration by alternative delivery routes to maximise therapeutic response. Oral dosage forms are intended usually for the systemic effects resulting from drug absorption through the various epithelia and mucosa of the gastro-intestinal tract. An oral route is the most frequently used route for drug administration.

This is due to the following reasons:

 Oral route is the most convenient and uncomplicated

 Ease of administration and safety

 Improved patient compliance

 Cost-effectiveness

Disadvantages include slow onset of action, possibilities of irregular absorption and destruction of drugs by enzymes and secretions of the gastro-intestinal tract. The most popular oral dosage forms are tablets, capsules, suspensions, solutions and emulsions.

Oral solid dosage forms such as tablets and capsules have been formulated and developed as they are the most effective routes of administration of a new drug. Nevertheless, it is probable that at least 90% of all drugs used to produce systemic effects are administered by the oral route. Tablets and capsules represent unit dosage forms in which one usual dose of the drug has been accurately placed.

Tablet dosage forms occupy the largest and the most significant place among all pharmaceutical dosage forms, and it considered one of the most popular drug delivery systems. The use of a glass of water to take the tablet is considered to be the easiest and most suitable technique of administration of the drug to a patient.

1.2. TABLETS ³

Tablets are defined as solid preparations intended for oral administration, each containing a single dose of one or more active ingredients. Tablets are prepared by compaction and contain drugs and formulation additives. They vary in shape and differ greatly in size and weight, depending on amount of medicinal substance and the intended mode of administration. Tablet may be coated or uncoated, consist of one or more active

(14)

1. INTRODUCTION

substances with or without excipients. The excipients include substances such as diluents, binders, disintegrant, glidant and lubricants, substances capable of modifying the behaviour of the preparation in digestive tract, colorants and flavouring substances. It is the most popular dosage form and 70% of the total medicines are dispensed in the form of tablet.

1.3.METHODS OF TABLET FORMULATION Tablets are prepared by,

 Direct compaction

 Granulation Methods

 Wet granulation

 Dry granulation 1.4. ADVANTAGES

 They are dosage form and offer the greatest capabilities of all oral dosage forms for the greatest precision and least content variability.

 Low cost among all oral dosage forms.

 They are the easiest and cheapest to package and ship.

 Product identification requires no additional processing steps when employing embossed or monogrammed punch face.

 Provides greatest ease of swallowing with the least tendency for hang up above the stomach.

 They lend themselves to certain special release profile products E.g. enteric coated or delayed release profiles.

 Easy large scale production than other oral dosage forms.

 They have the best combined properties of chemical, mechanical and microbiological stability among all the oral dosage forms.

 The emergency supplies of the drug can be conveniently carried by the patient.

1.5. DISADVANTAGES

 Drugs with poor wetting slow dissolution properties, intermediate to large dosages, optimum absorption high in the gastro intestinal tract or any combination of this features may be difficult or impossible to formulate and manufacture as tablet that will still provide adequate or full drug bioavailability.

(15)

1. INTRODUCTION

 Bitter tasting drugs, drugs with an objectionable odour or drugs that are sensitive to oxygen or atmospheric moisture may require encapsulation or entrapment prior to compression, or the tablets may require coating. In such cases, the capsules may offer the best and lowest cost approach ^[3].

1.6. TYPES OF TABLETS ²

Tablets are divided into classes based on their route of administration and their function.

1.6.1. Oral Tablets for Ingestion I. Standard Compressed tablets II. Multiple Compressed tablets

a) Layered tablets

b) Compression coated tablets c) Inlay tablets

III. Modified release tablets IV. Delayed action tablets V. Targeted tablets a) Floating tablets b) Colon targeted tablets VI. Chewable tablets

 Sugar coated tablets

 Film coated tablets

 Enteric coated tablets

 Chewable tablets

 Controlled release tablets 1.6.2. Tablets used in the Oral Cavity

 Buccal tablets

 Sublingual tablets

 Lozenges and Troches

 Dental cones

(16)

1. INTRODUCTION

1.6.3. Tablets administered by Other Routes

 Implantation tablets

 Vaginal tablets

1.6.4. Tablets used to prepare Solution

 Effervescent tablets

 Dispersible tablets

 Hypodermic tablets

 Tablet triturates ^[2].

1.7. PAEDIATRIC DOSAGE FORMS ⁴

The paediatric population is a heterogeneous group ranging from new-borns to adolescents with large physical and developmental differences regarding pharmacokinetics and pharmacodynamics. Organ maturation, metabolic capacity, skin maturation and other factors may change with age, especially in early infancy. The age groups identified by ICH have been derived mainly from physiological and pharmacokinetic differences from birth to adult:

The WHO has proposed the following age classification:

-Pre-term new-born infants (<37 weeks gestation) - Full-term new-born infants (0 to 28 days)

- Infants and toddlers (1 month to 2 years) - Children, pre-school (2 to 5 years) - Children, school (6 to 11 years)

- Adolescents (12 to 16-18 years -dependent on region-)

It is a challenge to find one formulation appropriate for all age groups. The aim should be to safely cover as wide an age range as possible with a single formulation.

Children cannot be considered as « small adults » as they present different anatomical and physiological characteristics. Current use of medicines for the paediatric population reflects the full range of dosage forms and routes of administration used for adult medicines.

Pharmacists, parents or caregivers are often faced with the need to manipulate an adult medicine in a way that is not described in the Summary of product characteristics. This can be rather simple, e.g. breaking tablets that do not have a score line with a tablet or complex, e.g. using tablets as a source for an active pharmaceutical ingredient (API) to prepare a

(17)

1. INTRODUCTION

suspension. Pharmacists may also be faced with the need to compound a medicine on the basis of the API.

The use of such medicines may expose children to overdosing and unintended side- effects or under dosing without the expected efficacy. Moreover, excipients that are safe for adults may not necessarily be so for children.

Safe and effective pharmacotherapy in paediatric patients requires the timely development of medicines and information on their proper use that suit the age, physiological condition and body sizes of the child. Formulations developed specifically for children are often needed.

Worldwide, the availability of licensed, paediatric drugs is lagging behind those for adults and the younger the child, the fewer drugs available. Even if a drug is licensed for paediatric use, it may not be suitable to administer all of the necessary (lower) doses, it may not be suitable for administering the drug to young children, or they may be poorly accepted.

Thus, health care professionals are often left with no other option than to prescribe drugs outside the approved conditions for age, indication, dose, dosing frequency and/or duration of use (i.e. off-label use); to recommend an unapproved modification of a drug product such as crumbling tablets and mixing these with food or drink (i.e. off-label use) or to compound a drug product in the pharmacy from a mixture of the drug substance and suitable excipients (i.e. unlicensed drug use). However, off-label and unlicensed drug use are normally not supported by the same level of clinical and pre-clinical evidence as drugs that are used within their approved label conditions. As a consequence, off-label and unlicensed drug use may result in altered efficacy rates and an increased risk for harm and hospitalization.⁵

1.7.1. Challenges:

 To provide dose flexibility and dose accuracy to overcome dysphagia,

 To meet the needs of a population with a wide range in physiological size and maturity,

 To ensure patient adherence for example by taste masking of the formulation.⁶ 1.7.2. Paediatric Drug Development: Dosing Aspects ⁵

Human growth is not a linear process. As such, children are not small adults, and paediatric doses cannot be calculated (extrapolated) as a standardized fraction of the dose for adults. Rather, the development and use of paediatric drugs requires specific knowledge on

(18)

1. INTRODUCTION

the age related aspects of the drug’s absorption, distribution, metabolism and elimination characteristics, i.e. pharmacokinetics (PK), as well as its receptor and organ interaction, i.e.

pharmacodynamics (PD). Moreover, it must be realized that the permeability and solubility of a drug substance in children may differ from adults, meaning that the Biopharmaceutical Classification System (BCS) must be used with caution.

When deciding on suitable dosing, other aspects which may have an impact on the PK/PD of a drug product in an individual child must be considered as well, e.g. genetic variability, maturity of enzymatic systems involved in metabolism, concomitant drug use and coexisting diseases, hypothermic treatment procedures, obesity.

Accurate dosing can only be assured when the pharmaceutical design of the drug product includes the recommended dose or allows this dose to be measured correctly, when the child is able and willing to use the drug product as intended and when the child’s caregiver is able and willing to administer the dose correctly and as recommended. Moreover, a flexible dosage form is required when minor changes in age, body weight and/or body surface result in different dosing recommendations.⁵

1.7.3. Needs and challenges in developing paediatric medicines.⁴

 Convenient, reliable administration

 Acceptability and palatability

 Minimum dosing frequency

 End-user needs

 Dosage forms to be considered in particular 1.7.3.1. Convenient, reliable administration

Paediatric medicines should preferably be presented as formulations that are ready to administer. The need to manipulate the dose by health professionals, parents or caregivers prior to administration should be kept to a minimum. However, there might be situations, depending on the formulation properties and the dose range to be covered, where this cannot be avoided.

Alternatively, for accurate dosing the dosage form should be designed to subdivide into smaller, uniform doses of appropriate size and in case of liquid forms the dose volume should be accurately measured.

(19)

1. INTRODUCTION

1.7.3.2. Acceptability and palatability

Acceptability is the overall acceptance of the dosage form regardless of the mode of administration. Palatability is the overall acceptance of the taste, flavour, smell, dose volume or size and texture of a medicine to be administered to the mouth or to be swallowed.

Palatability can be highly important to compliance.

1.7.3.3. Minimum dosing frequency

Parents and caregivers take care of the medication of young children while schoolchildren and adolescents can often manage the medication themselves. In both cases minimal dosing frequency should be attempted.

1.7.3.4. End-user needs

It is also important to bear in mind supply chain considerations such as ease of transportation and storage requirements. Storage in a refrigerator by the user is not always possible.⁴

1.7.3.5. Dosage forms to be considered in particular

Dosage forms that, in general, are likely to prove most suitable for global use, including for developing countries, and which should be prioritized, are flexible solid dosage forms such as tablets that are orodispersible and/or can be used for preparation of oral liquids suitable also for the younger age groups, e.g. dispersible and soluble tablets.⁴

1.8. MULTIPLE UNIT DOSAGE FORMS ⁷

Oral controlled release drug delivery systems are divided into two classes:

• Single unit dosage forms, such as tablets, capsules,

• Multi-unit dosage forms, granules, pellets or mini tablets.

In multi-unit dosage forms, the dose is divided into subunits and each unit contains the drug. The total dose is the sum of the drug in the subunits and the dose is dependent on the functionality of the subunits. Multi unit dosage forms are useful when the selected ingredients exhibit additive or synergistic effects or the dose can be reduced according to a single unit dosage form. After administration, the dosage units are spread to the stomach and gastrointestinal tract and the risk of local irritation is reduced as a result of an equal drug release. Multi-unit dosage forms show a more reliable dissolution profile than single units, which means better bioavailability.

(20)

1. INTRODUCTION

Table 1: Properties of multi unit and single unit dosage forms Multi Unit dosage Single unit dosage

More predictable gastric emptying

Gastric emptying with high variability

Gastric emptying is less dependent on

Gastric emptying is highly dependent on

nutritional status nutritional status Absorption grade does not

show intra-

Absorption rate and grade show intra-

and inter-individual variability and inter-individual variability Risks of overdose and local

irritation

Risks of overdose and local irritation

are lower are higher

Complex production

technologies Simple production technologies

1.9. MINI-TABLETS ⁸

Mini-tablets are flat or slightly curved tablets with a diameter ranging between 1.0-3.0 mm. They are usually filled into a capsule, occasionally compressed into larger tablets, or sometimes placed in sachets for easy administration.

Mini tablets will give reproducible plasma drug concentrations. Plasma drug concentration is directly proportional to the absorption. Absorption is more and even with mini tablets as they are distributed all over the surface which is not in case of single unit dosage forms. So by formulating multiple unit dosage forms like mini tablets better plasma drug profiles can be obtained. Mini tablets can be easily divided and administered without loss of activity. Elderly and paediatric patients who sometimes chew the tablets which releases drug all at once and may cause toxicity in case of normal tablet but in case of Mini tablets, they can be chewed as here each mini depot in the formulation act individually dose dumping may not occur. For local irritating drugs, mini tablet formulation decreases the irritation effect than that of single unit formulations.

(21)

1. INTRODUCTION

The EMA paediatric guideline states that small tablets (also referred to as mini- tablets) may be considered as a measure to improve acceptability and dosing flexibility in children, as several tablets can be taken as a single dose. However, it does not specify when tablets are to be considered as small, although a limit up to 5 mm has been proposed in the draft for public consultation. The guideline clearly indicates that, apart from size and shape, the suitability of small tablets should also be justified in relation to child health conditions, disease development and the risks associated with chewing, choking, aspiration and over- and under-dosing.⁵

Fig.1.Mini tablets and their packaging configurations.

In young children, the acceptability of oral formulations mini-tablets has already been discussed elsewhere. In summary, we have found that 4-mm uncoated mini-tablets can be used successfully in children from 1 year of age. In addition, Klingmann et al. showed that smaller 2-mm mini tablets can be used in infants from 6 months of age, whereas2 mm rapidly dissolving mini-tablets can be used as early as in the pre-term age. These studies actually indicated that mini-tablets are equally or even better accepted than oral syrups. Moreover, Kluk et al. confirmed that mini-tablets can be used as a flexible dosage form since children from 2 years of age were able to take 5 to 10 tablets in a fruity jelly on a spoon. Although the co-administration of medicines with food or drink is a common practice in children, concerns have been raised on the possible impact of the food or drink upon direct contact with the drug product. The concerns mainly relate to the possible effect on physical parameters such as the particle size or tablet coating or on the release of the active substance from the drug product, i.e. the drug product bio-availability.⁵

(22)

1. INTRODUCTION

Department of Pharmaceutics, COP, MMC, Chennai -03. Page 10 1.9.1. Advantages of the mini tablets ⁸

 Drug loading capacity is high.

 Formulation development is easy.

 Provides more uniform release kinetics. Thus, the risk of sudden increase in blood concentration is reduced.

 İntra and inter individual variability is low.

 The risk of local irritation is reduced because they spread throughout the gastrointestinal tract.

 Pellets are produced by fluid bed granulation or extrusion-spheronization methods, while mini tablets are produced by simple tablet production methods. This saves time and money.

 The absence of solvent use in production increases the stability.

 Superiority to granules

 Mini tablets have a smooth surface, stable surface area and high mechanical resistance compared to granules. It can be easily coated and requires less coating material than granules.⁷

1.9.2. Constituents of Mini-tablets ⁸

Different mini-tablets can be formulated and designed individually, incorporated into a capsule to release the drug at different sites and at different rates. Different combinations of mini-tablets include immediate release, delayed release, and/or controlled release formulations. Also, combining different mini-tablets together, incompatible drugs can be administered. This, as a result, improves overall therapeutic outcome, and also concurrent diseases can be treated effectively.

1.9.3. Release profile ⁸

 Due to increased surface in relation to volume, the drug can be released more efficiently in case of mini-tablets.

 By applying uniform layer of a retarding film coat, the release rate of the drug can be controlled with greater certainty.

 By combining different doses of mini tablets, it is possible to achieve various releases with one formulation.

(23)

1. INTRODUCTION

 Due to significant smaller dimensions of the mini tablets, when compared to normal tablets, they pass through the stomach at a more even rate. As a result, the

concentration of the drug in the blood can be easily reproduced.

1.9.4. Outlook ⁸

Mini-tablets could offer a solution to the current issue in the pharmaceutical industry that is lack of dosage forms for paediatrics. Mini-tablets can be considered as a potential new formulation for paediatric use, as they meet the requirements of child-friendly drug delivery.

In paediatric use, mini-tablets offer many benefits such as, the delivery of an accurate dose and the opportunity of dose flexibility by administering multiple mini-tablets.

1.9.5. Possibilities of Formulating Mini-Tablet Dosage Forms ⁸ 1. Compressed mini-tablets

2. Encapsulated Coated mini-tablets

3. Compressed mini-tablets presented as a biphasic drug delivery system.⁷ 1.9.6. Types of Mini tablets ⁹

Mini tablets can be classified based on the target site, method of manufacturing, patient needs as follows,

1. Paediatric mini tablets 2. Gastro retentive mini tablets 3. Bio-adhesive mini tablets 4. pH responsive mini tablets 5. Biphasic mini tablets

6. Oral disintegrating mini tablets 1.9.6.1. Paediatric mini tablets ⁹

Syrups, tablets and capsules are commonly used dosage forms for children. Syrups are liquid dosage forms which are simple to administer and dose can be easily altered to the patient needs on the other side disadvantages with these liquids dosage forms are chemical, physical, and microbial instability, taste issues, lack of controlled release and formulation problems. In case of tablets as they are big in size difficulty in swallowing and dose adjustment is difficult. Some time we have to break the tablets and administer which causes loss of activity of the tablets. Patient compliance is another issue with the conventional dosage forms.

(24)

1. INTRODUCTION

Department of Pharmaceutics, COP, MMC, Chennai -03. Page 12 To overcome all the above issues formulating mini tablets can result in good patient acceptance. Mini tablets are easily accepted by children than other dosage forms like tablets, syrups, and capsules etc.

1.9.6.2. Oral disintegrating mini tablets ⁹

Oral dispersible tablets (ODTs) are the novel dosage form which rapidly disintegrates in the mouth (1-3 min) without chewing upon oral administration and without the need of water, unlike other conventional oral solid dosage form14. Oral Dispersible Tablets (ODTs) are also known as “fast dissolve”, “rapidly disintegrating”, “quick-dissolve”, “crunch-melt”,

“bite-dispersible”, “mouth-dissolve”, and “oro dispersible” tablets .

Oral dispersible mini tablets (ODMTs) are more suitable for paediatric patients because of their small size, pleasant mouth feel and fast disintegration in mouth. The ODT should have the following characters they should disintegrate in the mouth without additional water. The disintegrated tablet should become a soft paste or liquid suspension, which can provide good mouth feel and smooth swallowing. Because ODTs dissolve or disintegrate in the patient’s mouth, the drug will be partially dissolved in close proximity to the taste buds. A pleasant taste inside the mouth becomes critical for patient acceptance. Unless the drug is tasteless or does not have an undesirable taste, taste-masking techniques should be used. The taste-masking technology should also be compatible with ODT formulations.

For example, if drug particles are coated to minimize unpleasant taste, the coating should not be broken during compression or dissolved during wet granulation. Taste masking of bitter tasting drugs is critical to the success of the ODT formulations. For the ideal ODT technology, the drug properties should not significantly affect the tablet property.

Because ODTs are designed to have a quick dissolution/disintegration time, the tablet porosity is usually maximized to ensure fast water absorption into the tablets. In addition, low compression pressure causes fast dissolving dosage forms to be soft, friable, and unsuitable for packaging in conventional blisters or bottles. A strategy to increase tablet mechanical strength without sacrificing tablet porosity or requiring a special packaging to handle fragile tablets should be provided. A good package design or other strategy should be created to protect ODTs from various environmental conditions especially from moisture.⁹

(25)

1. INTRODUCTION

Department of Pharmaceutics, COP, MMC, Chennai -03. Page 13 1.9.7. METHODS OF MANUFACTURING MINI TABLETS ⁹

Some of the methods that can be used for the manufacturing of mini tablets are 1. Direct compression

2. Dry granulation 3. Wet granulation 4. Melt- extrusion

Fig.2. Tabletting methods

Fig.3. Mini tablets tools

Fig.4: Types of staples used in mini tablet production.

mini ablet production (6).

(26)

1. INTRODUCTION

Department of Pharmaceutics, COP, MMC, Chennai -03. Page 14 1.9.7.1. DIRECT COMPRESSION ¹⁰

This method is used when a group of ingredients can be blended and placed in a tablet press to make a tablet without any of the ingredients having to be changed. This is not very frequent because many tablets have active pharmaceutical ingredients which will not allow for the direct compression due to their concentration or the excipients used in formulation are not conducive to direct compression.

Advantages of Direct Compression¹⁰ 1. Cost Effectiveness

2. Stability.

3. Faster Dissolution

4. Less wears & tears of punches 5. Simplified Validation

Limitations of direct compression¹⁰ 1. Segregation

2. Cost

3. Low dilution potential 4. Re-workability

5. Lubricant sensitivity 6. Variation in functionality 1.10. DISPERSIBLE TABLETS Definition ⁴

Dispersible tablets are uncoated or film-coated tablets that can be dispersed in liquid before administration giving a homogenous dispersion. Dispersible tablets usually disintegrate within three minutes when put in water or a small amount of breast milk.

Dispersible tablets are a convenient formulation for infants, toddlers and pre-school children.

1.10.1.Advantages of dispersible tablets versus liquid formulations ⁴ In general dispersible tablets are:

- More convenient for active pharmaceutical ingredients with insufficient stability in water.

- More easily transportable and they generate less handling and transportation costs for the same amount of active ingredient (less volume, less weight).

(27)

1. INTRODUCTION

Department of Pharmaceutics, COP, MMC, Chennai -03. Page 15 - Easier to produce and the production costs are less, which makes them more affordable than standard liquid formulations.

Other advantages include:

- can be used in very young children (0 – 6 months).

- are easy to dispense and: they require minimal manipulation by health professionals and parents prior to use which minimises the risk of errors.

- require a small amount of water for administration. - can be dispersed in breast milk.⁴ 1.11.Role of Disintegrant in the manufacturing of dispersible tablets ¹¹

Disintegrant are substances commonly included in tablet formulations and in some hard shell capsule preparations to benefit penetration and dispersion of the matrix of the dosage form in dissolution fluids. An oral solid dosage form should admirably disperse into the primary particles from which it was prepared. Disintegrant are the agents added to tablet (and some encapsulated) formulations to promote the breakup of the tablet (and capsule

“slugs’) into smaller fragments in an aqueous environment thereby increasing the available surface area and promoting a more rapid release of the drug substance.

1.11.1. Mechanism of Disintegrant ¹¹

There are four major mechanisms for tablets disintegration as follows Swelling

The most widely recognised general mechanism of action for tablet disintegration is swelling. Tablets with high porosity and lack of adequate swelling force show poor disintegration. On the other hand, tablet with low porosity exert sufficient swelling force. It is worthy to note that if the packing fraction is very high, fluid is unable to penetrate in the tablet and disintegration slows down.

Porosity and capillary action(Wicking)

Disintegration by capillary action is always the first step. When we add the tablet into suitable aqueous medium, the medium penetrates into the tablet and replaces the air absorbed on the particles, which weakens the intermolecular bond and breaks the tablet into fine particles. Water uptake by tablet banks on hydrophilicity of the drug/ excipients and on tabletting conditions. For these types of disintegrant sustenance of porous structure and low interfacial tension towards water is mandatory which helps in disintegration by creating a

(28)

1. INTRODUCTION

Department of Pharmaceutics, COP, MMC, Chennai -03. Page 16 hydrophilic network around the drug particles.

Due to disintegrating particles repulsive forces

Another mechanism of disintegration attempts to elucidate the swelling of tablet made with ‘non-swellable’ disintegrant. Guyot-Hermann has adduced a particle repulsion theory based on the observation that non-swelling particle also cause disintegration of tablets. The electric repulsive forces between particles make the basis for disintegration and water is required for it. Researchers found that repulsion is secondary to wicking.

Due to deformation:

During tablet compression, disintegrating particles get deformed and these deformed particles get into their normal structure when they come in contact with aqueous media or water. Occasionally the swelling capacity of starch was increased when granules were extensively deformed during compression. This increase in size of the deformed particles produces a breakup of the tablet.

1.11.2.The ideal disintegrant should have the following characteristics ¹²: 1. Poor solubility

2. Poor gel formation 3. Good hydration capacity

4. Good moulding and flow properties

5. No tendency to form complexes with the drugs 1.11.3. Factors effecting action of disintegrant ¹²

1. Percentage of disintegrant present in the tablets 2. Types of substances present in the tablets 3. Combination of disintegrant

4. Presence of surfactants 5. Hardness of the tablets.

6. Nature of drug substances 7. Mixing and screening

Because of the increased demands for improved dissolution requirements, there are currently, a new generation of “Super disintegrant”. These novel substances are more effective at lower concentrations with greater disintegrant swell, hydrate, change volume or form and produce a disruptive change in the tablet. Effective super disintegrant facilitate

(29)

1. INTRODUCTION

Department of Pharmaceutics, COP, MMC, Chennai -03. Page 17 improved compressibility, compatibility and have no negative impact on the mechanical strength of formulations containing high-dose drugs. They are widely used in wet granulation and direct compression applications.

1.11.4. Classification of superdisintegrants ¹³

Table.2 : Classification of Super disintegrant Structural type (NF

name)

Description Trade name

(manufacturer) Modified starches

(sodium starch glycolate, NF)

Sodium carboxy methyl starch; the carboxy methyl

groups induces

hydrophilicity and cross linking reduces solubility

Explotab® (Edward Mendell Co.), Primojel®

(Generichem Corp.), Tablo®

(Blanver, Brazil) Modified cellulose

(Croscarmellose, NF)

Sodium carboxy methyl cellulose which has been cross-linked to render the material insoluble.

AcDiSol® (FMC Corp.), Nymcel ZSX® (Nyma, Nertherlands),

Primellose® (Avebe, Netherlands) Solutab®

(Blanver,Brazil) Cross-linked polyvinyl

pyrrolidone

(Crospovidone, NF)

Cross-linked

Polyvinyl pyrrolidone; the high molecular weight and cross-linking render the material insoluble in water.

Crospovidone M®

(BASF Corp.), Kollidon CL® (BASE Corp.), Polyplasdone XL (ISP Corp.

Three major types of compounds have been developed which swell to many times their original size when placed in water while providing minimal viscosity effects.

1. Modified starches – Sodium Carboxy methyl (Chemically treated Potato Starch) starch i.e. Sodium Glycolate (Explotab, Primogel)

Mechanism of action: Rapid and extensive swelling with minimum gelling.

Effective Concentration: 4-6%. Above 8% disintegration times may actually increase due

(30)

1. INTRODUCTION

Department of Pharmaceutics, COP, MMC, Chennai -03. Page 18 to gelling and its subsequent viscosity providing effects.

2. Cross-linked polyvinyl pyrrolidone - water insoluble and strongly hydrophilic i.e., Crospovidone (Polyplasdone XL, Kollidon CL)

Mechanism of action: swelling, water wicking and possibly some deformation recovery.

Effective Concentration: 2-4%

3. Modified Cellulose – cross-linked form of Sodium carboxy methyl cellulose internally.

i.e., Ac-Di-Sol (Accelerates Dissolution), Nymcel

Mechanism of action: wicking because of fibrous structure, swelling with minimum gelling.

Effective Concentration: 1-3% (Direct Compression), 2-4% (Wet Granulation) Table 3: Example of Commercially Available Mini-tab Products in USA¹⁴

Brand Name Drug Name Indication Manufacturer Dosage Form Rythmol® SR Propafenone

HCl

Antiarrhythmic GlaxoSmithKline Capsule

Enzym-Lefax® Pancreatin Indigestion Bayer Capsule

Lamisil® Oral Granules

Terbinafine HCl

Antifungal Novartis Sachet

Orfiril® long Sodium Valproate

Epilepsy Desitin Capsule,

Sachet Pankreatan® Pancreatin Pancreatic

Insufficiency

Novartis Capsule

Trilipix® Fenofibric acid Cholesterol Abbott Capsule

(31)

2. LITERATURE REVIEW

Department of Pharmaceutics, COP, MMC, Chennai – 03. Page 19 REVIEW OF LITERATURE

On the basis of technology and method research articles were referred as following

1. Seyed Alireza Mortazavi a, et al,^[15]formulated direct compressed Ciprofloxacin mini tablets for ocular use to obtain prolonged and controlled drug release to the anterior eye segment. Seven formulations of Ciprofloxacin along with various amounts of different sustained release cellulose derivatives (HPMC, Na CMC, HEC and EC), carbopol 974P, solubilizer and lubricant were directly compressed into minitablets, using concave 3 mm diameter punches. All the prepared formulations were evaluated in terms of physicochemical tests, including uniformity of weight, friability, crushing strength, water uptake and in-vitro drug release studies and it was revealed that the type and amount of cellulose derivatives used can influence the rate of drug release. The finally selected formulation (B3 ) contained ethyl cellulose, carbopol 974P, Mannitol, Sodium stearyl fumarate and Ciprofloxacin, which showed more than 80% drug release over a period of 5h. Based on kinetic studies, formulation B3 was found to best fit the zero order equation. Hence, overall formulation B3 was concluded as the best formulation.

2. Mirelabodea, Ioan Tomuţă , Sorin Leucuţa., ^[16] formulated Metoprolol mini tablets 3mm by dry granulation method. 7 formulations of metoprolol dose 8.6 mg were prepared with excipients as PVP K 30; Lactose monohydrate, pregelatinised starch–Starch 1500, co-processed excipient - Cellactose 80 spray-dried lactose, magnesium stearate, silicon dioxide and glyceryl behenate. The prepared tablets were evaluated for physico chemical parameters like weight variation, hardness, friability, drug content, in-vitro release. The optimized formulation F4 was shown the results of drug content 97.05% and drug release 99.82%.

3. Stoltenberg , J. Breitkreutz., ^[17] formulated and evaluated the direct compressed Hydrochlorothiazide oral disintegrating mini-tablets as a suitable dosage for paediatrics use. Five formulations were made with commercially available ready to use tabletting excipients (Ludiflash, Parteck ODT, Pearlitol Flash, Pharmaburst 500 and Prosolv ODT) and Hydrochlorothiazide dose of 1 mg (15.4%) per one mini tablet were formulated. The compression process parameters were optimized for 2mm mini tablets using rotary tablet press. All the formulations were evaluated of the

(32)

Department of Pharmaceutics, COP, MMC, Chennai – 03. Page 20 parameters as flow properties, crushing strength, friability, mass variation and simulated wetting time. For formulations with HCT, Ludiflash results in a sufficient crushing strength of 8.1 N and a low SWT time of 4.9 s for the formulation compressed at 8 kN .

4. Anusha N, et al,^[18]formulated and evaluated Venlafaxine Hydrochloride mini tablets filled hard gelatin capsules. The mini-tablets were prepared by wet granulation method using HPMC K4M, HPMC K100M, HPMC K200M, each mini tablet containing 10 mg Venlafaxine. The prepared mini tablets were evaluated physical parameters such as thickness, weight variation, friability, hardness and drug content and In-vitro drug release. Formulation F2 was shown at the end of 12^th hrs 100%

release was found.

5. Kiran V. Jadhav, et al,^[19] developed and validated new, simple ultraviolet (UV) spectrophotometric method of Cefprozil in bulk and pharmaceutical dosage form and its application to study its stress degradation behavior. The absorbance maxima peak was found at 280 nm.

6. H. Lou et al,^[20] formulated mini-Tablet of co-grinded Prednisone–Neusilin US2 Complex (Amorphous Magnesium Aluminometasilicate) for Paediatric Use. The prepared Prednisone–NeusilinUS2 complex was co-grinded at various ratios (1:1, 1:3, 1:5, and 1:7) and formulated into a 2-mm diameter mini-tablet. To improve taste masking and stability, mini-tablets were coated by dip coating with Eudragit® EPO solution. Co-ground prednisone–NeusilinUS2 (1:7) complex yielded reliable and reproducible preparation processes for mini-tablets.

7. Kiran V Mahajan, et al,^[21]designed and evaluated mini tablets of Ramipril as a bi phasic system by directly compressed method. Total 9 formulations were prepared, biphasic release containing 11mg of Ramipril with different proportion of hydroxyl propyl methyl cellulose and Ethyl cellulose and fast releasing component containing sodium starch glycolate, croscarmellose sodium as super disintegrant. The prepared mini tablets were evaluated physical parameters such as thickness, weight variation, friability, hardness and drug content and in-vitro drug release. Formulation F5 was shown at the end of 2 hrs near about half percent release found 47.88±0.55% after 12hrs found 96.23±1.41%.

(33)

Department of Pharmaceutics, COP, MMC, Chennai – 03. Page 21 8. Raja Subburayalu., et al,^[22] formulated an extended release formulation of Clopidogrel bisulphate into mini-tablets coated with a combination of pH dependent polymer, pH independent polymer and pore former to improve the bioavailability of Clopidogrel. Eight formulations of Clopidogrel core mini tablets were prepared using tartaric acid, mannitol, microcrystalline cellulose and hypromellose E5 by dry granulation method and it was compressed using 2.5mm multi-tip punch with the target weight of 20mg/unit and 8 units/unit formulation (F37), coated with the ratio of 60:25:15 (ethocel 7cps: hypromellose phthalate 50: hypromellose 5cps), shown the better release of 32% in acid for 1hr, to achieve the loading dose, and the extent of 100% release at 12hr, in pH 6.5 phosphate buffer. The core tablets were coated with Opadry AMB as barrier and controlled release coating was done by using different ratio’s of hypromellose phthalate, ethyl cellulose, hypromellose.

9. P. Sandhya, et al,^[23]formulated and evaluated of Repaglinide biphasic mini tablets.

Total 6 formulations of immediate release mini tablet (IRMT) were prepared by direct compression using sodium starch glycolate, croscaromellose sodium as super disintegrant, each mini tablet containing 2mg Repaglinide. The percentage drug released in the first 30 min was similar in the all formulations. However, in IRMT IF2, 99.7 % of the Repaglinide was released within the first 15 min. 11 batches of Sustained release mini tablet (SRMT) were formulated using HPMC K4M, HPMC K15M, HPMC K100M, ethyl cellulose, each mini tablet containing 4mg Repaglinide.

In-vitro release tests were carried out for SRMT, the optimized formulation SRMT SF11 was released 90% of the Repaglinide within 8 hrs and 96.23 % within 10 hrs.

10. Abdul Mannan, et al,^[24] formulated and evaluated Orlistat fast disintegrating mini- tablets for the treatment of Obesity. The prepared 3mm mini-tablets each containing 6mg of Orlistat using Orlistat β-cyclodextrin (1:2M) complex. Total 9 formulations were prepared, the optimized formulation containing the 40% of ludiflash (mannitol) results the disintegrating within 55 seconds and released the 86% of drug within 10 minutes. The comparative in-vitro dissolution study with the existing marketed product the optimized formulation (ORDT-9) was released three fold faster and complete drug was released in the 15 minutes.

(34)

Department of Pharmaceutics, COP, MMC, Chennai – 03. Page 22 11. Natarajan R, et al,^[25] formulated and evaluated of compressed mini-tablets of Tramadol hydrochloride as a biphasic Drug Delivery System. 4 batches of mini- tablets were prepared by using drug with HPMC and EC. Tramadol hydrochloride compressed mini tablets were evaluated for various physical parameters namely thickness, hardness, friability, weight variation, etc. The results of testing both HPMC and EC indicated that the HPMC releases the drug with in the 8 hours but the EC containing formulations shown the sustained release upto 12 hours. Hydrophilic matrix of HPMC was sustained the drug release only upto 8 hours. A hydrophobic matrix of EC was better system for sustained delivery of a highly water soluble drugs like Tramadol hydrochloride for prolonged period.

12. Volnei Jose Tondo Filho, et al,^[26]formulated multiparticulate system containing enteric release mini-tablets of Omeprazole. 2 batches of 3mm mini tablets each containing 1.5 mg of Omeprazole with sodium starch glycolate, microcrystalline cellulose, magnesium carbonate, spray dried lactose formulated by direct compression method. Further, the core tablets were coated using pH dependent polymer hydroxyl propyl methyl cellulose / Eudragit® L30D55 in a fluidized bed coating method. The prepared mini tablets were evaluated physical parameters such as thickness, weight variation, friability, hardness and drug content and in vitro drug release. The formulation B2 shown good control of the release of the drug.

13. Sally A. El-Zahaby, et al,^[27] formulated and evaluated gastro retentive levofloxacin floating mini-tablets-in-capsule system for eradication of Helicobacter pylori. 5 batches of mini tablets 4mm diameter containing levofloxacin with different concentrations of HPMC K100M were prepared by wet granulation method. The prepared mini-tablets were evaluated for weight variation, thickness, friability, hardness, drug content, in vitro buoyancy, and water uptake and in-vitro release. The optimized formulation (F1) offered best LVF controlled release along with floating lag time <1 s and total floating time >24 h.

14. Khalid M. El-Say, et al,^[28] formulated and evaluated the Risperidone oral disintegrating mini-tablets for paediatrics use. A three-level three-factor Box-Behnken experimental design was employed to statistically and 15 formulations with 2mm minitablets were prepared using sodium starch glycollate, croscarmellose sodium and

(35)

Department of Pharmaceutics, COP, MMC, Chennai – 03. Page 23 microcrystalline cellulose as super disintegrant All OD-mini-tablet disintegration times were in the range from 1.68 and 17.97 s (formula F7) to 15.91 and 103.92 s (formula F5) in SSF and skimmed milk formula, respectively.

15. Dina M. Gaber, et al,^[29] formulated and evaluated mini-tablets versus pellets as promising multiparticulate modified 2 release delivery systems for highly soluble drug of Venlafaxine Hcl. Two formulations of mini tablets 2mm (MT1 & MT2) as well as pellets (FP1 & FP2) containing 30% w/w Venlafaxine with ethyl cellulose were prepared by wet granulation method. The physicochemical characteristics of all the prepared batches were evaluated. Mini-tablets represent a superior alternative to pellets as controlled release multiparticulate delivery system. Upon storage, mini- tablets ensured better shelf stability compared to pellets.

16. Talath Fatima, et al,^[30] formulated and evaluated of time dependent release of Montelukast tablet using mini tablet technology is to enhance and prolong the bioavailability of Montelukast via, first pass mechanism. Total 20 formulations of both SRMT & IRMT prepared using Montelukast Sodium with 10 % croscarmellose sodium as disintegrant and coated with HPMC, ethyl cellulose by wet granulation method. The physicochemical characteristics of all the prepared batches were evaluated. CMTICS-3 and CMTICS-11 were considered as the best formulations releasing Montelukast both as immediate (26.47 % and 25.99 % in an hour respectively) and as a sustained-manner and also shown better release at the end of 24hrs (97.07% and 98.74% respectively).

17. Gulnur Yeleken, et al,^[31] developed direct compressed Loratadine mini tablets as an alternative dosage form for paediatric use. Seven formulations with a loratadine dose of 0.5 or 1 mg per one mini tablet were prepared and compression process parameters were optimized for 2 and 3 mm mini tablets and for 5 mm tablets using a single punch Gamlen Tablet Press. Formulation F3, F5 and F6 minitablets disintegrated in about 30 sec and dissolution of loratadine in 500 ml of 0.1M hydrochloric acid was very fast, with at least 80% of the declared dose released within 3 min.

(36)

Department of Pharmaceutics, COP, MMC, Chennai – 03. Page 24 18. Kiran Kumar, et al,^[32] designed and evaluated floating mini matrix tablets of Pyridoxine Hydrochloride. 15 batches of floating mini matrix tablets of pyridoxine hydrochloride were formulated using hydroxy propyl methyl cellulose K grade polymers along with ethyl cellulose by wet granulation method. The physicochemical characteristics of all the prepared batches were evaluated. The optimized formulations FP8 has shown less floating lag time and more in vitro drug release profile.

19. Joana T. Pintol, et al,^[33]formulated and evaluated the ability of powdered milk to produce mini-tablets to deliver Paracetamol in paediatrics. Total eight combinations of four different tableting formulations compacted at two distinct forces using Whole milk powder, Paracetamol, sodium croscarmellose, D-mannitol, and magnesium stearate. Mini-tablets containing more Paracetamol disintegrated almost instantly resulting in more than 90% drug release within the first 2 minutes of test.

20. Mahipal Reddy Donthi, et al,^[34] formulated direct compressed famotidine floating multi unit of mini tablets. Five formulations of Famotidine mini tablets were prepared with matrix polymers like POLYOXWSR 1105 and HPMC K4M using multi stationary rotary compression machine with 3 mm flatted punches. The prepared tablets were evaluated for physico chemical parameters like weight variation, hardness, friability, buoyancy studies, drug content, in vitro dissolution and muco adhesive property in porcine gastric mucosa and also within the acceptable limits as per USP. The optimized formulation F5 exhibited floating lag time of 10 ± 2 sec with total floating time of 12 h and in vitro release profile of 99.14 ± 3.21% in 12 h.

21. Dhumane Poonam Shivaji, et al,^[35]formulated and characterized Norfloxacin ocular mini tablets as controlled drug delivery system. Three batches of 4mm mini tablets each containing 1.2 mg of Norfloxacin with HPMC K4(different ratio), carbopol 974, lactose DC and magnesium Stearate were formulated by direct compression method. The prepared mini tablets were evaluated physical parameters such as thickness, weight variation, friability, hardness and drug content and in vitro drug release. The batch C was shown maximum drug release and anti bacterial activity when compared with marketed product.

(37)

3. AIM AND OBJECTIVE OF THE STUDY

Department of Pharmaceutics, COP, MMC, Chennai -03. Page 25 AIM AND OBJECTIVES OF THE STUDY

AIM OF THE WORK

1. To prepare and evaluate orally disintegrating mini tablets of Cefprozil for paediatric use

2. Development of orally disintegrating mini tablets with:-

 Dose flexibility and dose accuracy,

 Meet the needs of a population with a wide range in physiological size and maturity,

 Taste masking of the formulation.

 Exhibit better physical, chemical and microbiological stability in comparison with liquids, which are considered as standard form in paediatric pharmacotherapy.

OBJECTIVE OF THE WORK

1. To select a suitable type and amount of disintegrant for the orally disintegrating mini tablets of Cefprozil.

2. To study compatibility of drug with excipients

3. To formulate orally disintegrating mini tablets of Cefprozil.

4. To evaluate the formulated orally disintegrating mini tablets of Cefprozil. (Post compression studies)

5. To evaluate the stability studies for optimized formulated orally disintegrating mini tablets of Cefprozil.

(38)

Department of Pharmaceutics, COP, MMC, Chennai -03. Page 26 Plan of Work:

Fig.5. Flowchart for Plan of Work Literature Survey

Selection of Drug and Excipients

Characterization of API

Melting Point, UV Spectroscopy, FTIR.

Formulation of Cefprozil Orally Disintegrating Mini tablets

Post compression studies of formulated Cefprozil Orally Disintegrating Mini tablets

Preformulation Studies Physical compatibility Study Chemical Compatibility Study -FTIR

Stability Studies for the Optimized formulation

(39)

Department of Pharmaceutics, COP, MMC, Chennai -03. Page 27 3.2. PLAN OF WORK

 Preformulation studies

 Raw material analysis

 Physical and chemical compatibility studies

 Standard Curve for Cefprozil

 Pre-compression studies of drug and blends

 Bulk density

 Tapped density

 Angle of repose

 Carr’s index

 Hausner’s ratio

 Formulation of orally disintegrating mini compressed tablets of Cefprozil.

 Post compression studies

 Physical appearance

 Uniformity of weight

 Hardness, thickness, diameter

 Friability

 Disintegration test

 Determination of drug content of tablets

 Content uniformity

 In vitro dissolution studies

 Stability studies