Formulation And Development

FORMULATION AND DEVELOPMENT

DOSAGE FORM CONSIDERATIONS

SCHEDULE Y APPENDIX-I

Data to be submitted along with the application to conduct clinical trials /import/manufacture of new drug for marketing in the country .

• Introduction • Chemical and pharmaceutical information 2.1

Information on active ingredients Drug information (Generic name,Chemical name or INN) 2.2 Physicochemical data a. Chemical name and structure  Empirical formula  Molecular weight b. Physical properties  Description  Solubility  Rotation  Partition coefficient  Dissociation constant

2.3 Analytical data      

Elemental analysis Mass spectrum NMR spectrum IR spectra UV spectra Polymorphic identification

2.4 Complete monographic Specification include    

Identification Identity/quantification of impurities Enantiomeric purity Assay

2.5 Validations   

Assay method Impurity estimation method Residual solvent/other volatile impurities

2.6 Stability studies(addnl details in app IX)  

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Final release specification Reference standard characterization Material safety data sheet

2.7 Data on formulation    

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Dosage form Composition Master manufacturing formula Details of the formulation(including active ingredients) In process control check Finished product specification Excipient compatibility study Validation of the analytical method

Comparative evaluation with international brand(s) or approved indian brands,      

If applicable Pack presentation Dissolution Assay Impurities Content uniformity pH

Force degradation study Stability evaluation in market intended pack at proposed storage conditions Packing specifications

WHAT IS FORMULATION? The conversion of a drug in to dosage form using suitable pharmaceutical ingredients and excipients.

NEED FOR DOSAGE FORM ACCURATE DOSAGE COATED TABLETS AND SEALED AMPULES ACID RESISTANT CONCEAL TASTE INSOLUBLE AND UNSTABLE SUBSTANCES IN SUITABLE VEHICLE

CLEAR LIQUID DOSAGE FORMS(SYRUPS) RATE CONTROLLED TOPICAL APPLICATIONS INSERT DRUG IN TO ONE OF THE BODY ORIFICES(SUPPOSITORIES) PLACEMENT OF DRUG DIRECTLY IN TO BODY FLUIDS(INJECTIONS) INHALATIONS THERAPY

GENERAL CONSIDERATIONS DRUG RELEASE PROFILE BIOAVAILABILITY CLINICAL EFFECTIVENESS THERAPEUTIC CONSIDERATIONS    

NATURE OF ILLNESS MANNER IN WHICH IT IS TREATED AGE ANTICIPATED CONDITION OF THE PATIENT

DIFFERENT TYPES LIQUID DOSAGE FORMS  SOLUTIONS  ORAL SOLUTIONS  SYRUPS  ELIXIRS  PARENTERALS  SUSPENSIONS  EMULSIONS

The drug molecule is dissolved or suspended in the liquid vehicle

SOLID DOSAGE FORMS POWDERS TABLETS  

SUSTAINED RELEASE ENTERIC COATED

CAPSULES  

HARD GELATIN SOFT GELATIN

SEMISOLID DOSAGE FORMS OINTMENTS SUPPOSITORIES PESSARIES CREAMS

INHALATIONS AEROSOLS

CONSTITUENTS OF A DOSAGE FORM DRUG VEHICLE PHARMACEUTICAL INGREDIENTS AND EXCIPIENTS

DRUG DATA FROM PREFORMULATION STUDIES eg:solubility data stability data etc.

PHARMACEUTICAL INGREDIENTS ANDEXCIPIENTS Produce drug in to final dosage form Solutions 

   

Solvents to dissolve the drug substances Flavors and sweeteners Colorants Preservatives Stabilizers

TABLETS      

Diluents and fillers Binders Antiadherents or lubricants Disintegrating agents Coatings Semisolid dosage forms

SEMISOLID DOSAGE FORMS 

Pharmaceutical bases

pharmaceutical excipients Non propreitary,chemical,commercial names Empirical and chemical formulae Pharmaceutical specifications Chemical and physical properties Incompatibilities Interactions with other excipients and drug substances Regulatory status Application in pharmaceutical

HARMONIZATION OF STANDARDS As per four Pharmacopeias    

U.S.P – N.F B.P European Pharmacopeia Japaneese Pharmacopeia

PALATABILITY Liquids by oral route Mask the disagreeable taste Capsule or coated tablets Chewable tablets to be sweetened and flavored Prediction of taste characteristics of a new drug is speculative

SELECTION OF FLAVORING AGENT Taste of drug substance itself 

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Cocoa flavored vehicles – mask bitter taste Cinnamon,orange,raspberry and other flavors – salty drugs more palatable

FACTORS IN SELECTION AGE 

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Children – sweet candy like preparations with fruity flavours Adults –less sweet prepns

FLAVORS CONSIST OF 

Oil or water soluble liquids and dry powders

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Oil soluble carriers – soyabean and other edible oils

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Water soluble carriers- water, ethanol , propylene glycol, glycerine and emulsifiers

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Dry carriers include – maltodextrins, cornsyrup solids,modified starches , gumarabic , salts,sugars and whey protein.

Flavors degrade by exposure to     

Light Head space oxygen Temperature Water Enzymes

Types of flavor : According to code of Federal regulations under Food Drug and Cosmetics Act  

Natural Artificial

COLOURING AGENTS USED FOR ESTHETIC ENHANCEMENT TYPES  INHERENT eg: Sulfur(yellow),riboflavin(yellow),cupric sulfate(blue),ferrous sulfate(red). 

AGENTS USED AS COULOURANTS 

synthetic and natural

Mineral source : 



eg: Zinc oxide is used to impart pink color to calamine Derivatives of aniline

REGULATIONS FOR USE Food and Drug Act in 1906 : Few colorants certified or permitted. Federal Food ,Drug and Cosmetics Act of 1938 as amended in 1960 .

Certified colours classified based upon their use 

FD&C color additives

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D&C color additives

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External D&C color additives

TOXICITY STUDIES Study protocol usually call 2 year study Long term toxicity and carcinogenicity Five categories : 

 

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Clear evidence of carcinogenic activity Some evidence Equivocal evidence indicating uncertainty

CERTIFICATION STATUS CONTINUALLY REVIEWED AND CHANGES ARE MADE  

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WITHDRAWL OF CERTIFICATION TRANSFER OF COLORANT FROM ONE CERTIFICATION CATEGORY TO ANOTHER ADDITION OF NEW COLORS TO THE LIST

IDEAL CHARACTERISTICS SAFE MUST NOT INTERFERE WITH THERAPEUTIC EFFICACY MUST NOT INTERFERE WITH PRESCRIBED ASSAY PROCEDURE

TYPES DYES – LIQUID DYES 

COLORANTS IN THE RANGE 0.0005% TO 0.001%

LAKE PIGMENT 

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A FD&C lake is a pigment consisting of a substratum of alumina hydroxide on which dye is adsorbed or precipitated 10 to 40% of colorant is used.

LAKES FINE DISPERSIONS OR SUSPENSIONS PARTICLE SIZE RANGE 1microM to 30microM LESSER CHANCE OF SPECKLING WITH FINER PARTICLES VEHICLES USED : Glycerin,propylene glycol,sucrose based syrup

COLORANTS IN CAPSULES COLORED EMPTY GELATIN CAPSULES TWO COLORED CAPSULE 0.1% DYE IS USED

CONSIDERATIONS SOLUBILITY pH pH stability of the preparation to be colored PHOTOSTABLE :stored in amber colored bottles OXIDATION POTENTIAL