SEMINAR ONPHYSIOCHEMICAL

FACTORS INFLUENCING FORMULATION

PRESENTED BY:-VBMROLL :- 12YEAR-2010-2011

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PREFORMULATION

What it is?

It is defined as phase of research and development in which preformulation scientist characterize physical & chemical properties of new drug molecule in order to develop safe, effective, and stable dosage form.

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DIRECT BENEFITS

Gives direction for development of formulation in choice of dosage form, excipients, composition, physical structure

Helps in adjustment of Pharmacokinetics and biopharmaceutical properties.

Support for process development of drug substance (yield, filtration...).

Produce necessary and useful data for development of analytical methods.

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CONTENTS:-

I. PHYSICAL CHARACTERISTICS

A. BULK CHARACTERISTIC

1) Crystallinity and Polymorphism

2) Hygroscopicity

3) Particle Size & Surface Area

4) Flow properties & Bulk density

5) Compressibility

6) Drug- Excipient Compatibility 

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B. SOLUBILITY ANALYSIS

1) Ionization constant2) Solubilization.3) Partition Coefficient4) Thermal effect5) Common ion effect.6) Dissolution.

C. STABILITY ANALYSIS1) Solid State Stability.2) Solution State Stability

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II. CHEMICAL CHARACTERISTIC

1) Oxidation.

2) Hydrolysis.

3) Photolysis.

4) Racemization.

5) Polymerization.

6) Isomerization.

7) Decarboxylation.

8) Enzyme Decomposition.

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CHRYSTALLINITY AND POLYMORPHISM Crystal habit (i.e outer appearance of the crystal) and the

Internal structure (i.e molecular arrangement within the solid) can affect physicochemical property of the drug

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BMCP

•Molecules are arranged in 3D•Prepared by slow precipitation•Low thermodynamic energy so low solubility rate

•Molecules are randomly arranged•Prepared by rapid precipitation•Higher thermodynamic energy so higher solubility rate

POLYMORPHISM:-

It is defined as the ability of a compound to crystallize in more than one crystalline form

Chemical stability and solubility changes due to polymorphism For e.g chloramphenicol palmitate exists in three (A,B,C)

polymorphic form, from which B is more soluble and melting point, density and hardness will also change 

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HYGROSCOPICITY

Some drugs have the tendency to adsorb atmospheric moisture

Now the amount of adsorb moisture depends upon the atmospheric humidity, temperature, surface area and the mechanism for the moisture uptake

The change in moisture level greatly influences chemical stability, flowability, and compactability.

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PARTICAL SIZE AND SURFACE AREA lt affects the bulk flow, formulation homogenicity of the drug

particles Each drug particle is tested for the smallest particle size as it

facilitates preparation of homogenous mixture Instruments used for checking the size and shape are Light microscope - Hemacytometer slide Coulter counter - Samples are dispersed in the conducting

medium such as isotonic saline and a few drops of surfactant, than 0.5 to 2 mi of this suspension is drawn into tube through small aperture across which voltage is applied and the particle passing through the hole is counted

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FLOW PROPERTY AND BULK DENSITY

Bulk density is of greatest important in the size of high dose capsule product and in a low dose formulation in which there is a large difference in drug and excepients density.

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IONIZATION CONSTANT(pKa):-

75% of all drugs are weak base 20% are weak acids and only 5% are non ionic amphoteric or alcohol

Henderson-Hasselblach equation:- pH = pKa + log[ionised form]/ [unionised form] ---for acids pH = pKa + log [unionised form] / [ionised form]---for base

Uses of this equation To determine pKa. To predict solubility of any pH provided that intrensic

solubility(Co) & pKa are known To facilitate the selection of suitable salt forming compounds To predict the solubility and pH properties of the salt

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METHODS TO DETERMINE pKa

Potentiometric method Conductivity method Dissolution rate method Liquid liquid partition method Spectrophotometric method

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SOLUBILIZATION

Many different approaches have been developed to improve drug solubility

Micronization:- Eg. Griseofulvin shows increased solubility by reducing particle

size Change in pH:- Eg. Solubility of Nimesulide increases as pH is increased Eg. Arginine increases solubility of coumarins Eg. Etoposide formulation is difficult because of its poor

solubility & liable chemical stability so etoposide loaded emulsion (ELE) is formulates most stable at pH 4-5

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Cosolvency

Addition of a water miscible solvent can often improve the solubility of a weak electrolyte or non-polar compound in water by altering the polarity of the solvent

Limited choice due to possible toxicity & irritancy. Ideally suitable : Dielectric constant (near to 80) Water / ethanol : most widely used system

Solubilization by surfactant:- Eg. Gelucire 44/14 is a surface active excepient that can

solubilize poorly soluble drug. Eg. Anionic and cationic surfactant exhibit drramatically higher

solubilization of gliclazide, while nonionic surfactant showed significantly lower solubilizing ability.

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Complexation:- Eg. The complexation of iodine with 10-15% pvp can improve

aq. Solubility of active agent

Use of metastable polymorphs:- Eg. B form of chloramphenicol palmitate is more water soluble

than A & C forms.

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PARTITION COEFFICIENT When a solute is added to two immisible liquid it will distribute

itself between two phase in a fixed ratio, which is referred to as partition or distribution coefficient.

Various organic solvents used in determination of partition coefficient include chloroform, ether, amyl acetate, etc.

In formulation development, the n-octanol/water partition coefficient is commonly used

p= (Concentration of drug in octanol)(Concentration of drug in water)------ For unionizable

drug

p= (Concentration of drug in octanol)(1-alpha) (Conc of drug in water)----- For ionizable drug

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p>1 – lipophillic drug P<1 – Hydrophillic drug

Methods to determine P:- Shake flask method Chromatographic method (TLC, HPTLC) Counter current and filter probe method

Applications of P:- Measure of lipophillic character of molecule Recovery of antibiotics from fermentation broth Extraction of dosage from biological fluid Absorption of drug from dosage form Study of distribution of flavoring oil between oil & water in

emulsion

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THERMAL EFFECT

Effect of temperature on the solubility of drug can be determind by measuring heat of solution (▲Hs)

ln S = - ▲Hs/R*T + c| Where S= Molar solubility at temp T (0K)

R= Gas constant If Hs is positive than increase In temperature increases the

drug solubility and vice-versa Heat of solution represents the heat released or absorbed

when a mole of solute is dissolved in a large quantity of solvent.

Typical temp. range should include 50C, 250C, 370C, & 500C. Important: Determination of temp effect on solubility helps in

predicting storage condition & dosage form designing

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COMMON ION EFFECT:-

To identify a common ion interaction IDR of HCL salt should be compared between

a) Water and water containing 1.2% W/V NaCL

b) 0.05 M HCL & 0.9% NaCl in 0.05 M HCl.

Both saline media contains 0.2 M CL- which is typically encountered in fluids in vivo

DISSOLUTION The adsorption of solid drugs administered orally can be

understood by following flow chart

Solid drug in GI fluid

Solution of drug in GI fluid

Drug in systemiccirculationDissolution Absorption

Kd Ka

When Kd<<<<<Ka absorption is dissolution rate limited

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Dissolution rate can affect:- Onset of action Intensity of action Duration of response Control the overall bioavaibality of drug form

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STABILITY ANALYSIS

Development of a drug substance into a suitable dosage form repairs the preformulation stability studies as:

[1] Solid state stability

[2] Solution state stability

Solid state stability:- Solid state reactions are much slower and more difficult to

interpret than solution state reactions because of reduced no. of molecular contacts between drugs and excepient molecules and occurrence of multiple reactions

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Technique for solid state stability studies: Solid state NMR Spectroscopy (SSNMR) Powder x-ray diffraction (PXRD) Fourier transform IR (FTIR) Raman Spectroscopy Differential scanning calorimetry (DSC) Thermo gravimetric analysis (TGA) Dynamic vapour sorption (DSV) SOLUTION STATE STABILITY The primary objective is identification of conditions necessary to form a stable

solution These studies include the effects of

-pH -Oxygen

-Light -Temperature

-Ionic strength -Coosolvent

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If the result of this solution stability studies dictate the compound as sufficiently stable, liquid formulations can be developed.

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Chemical Characteristic

OXIDATION It is very common pathway for drug degradation in both

liquid and solid formulation Oxidation occurs in two ways

1. Auto oxidation2. Free radical oxidation

Functional group having high susceptibility towards oxidation:-

Alkenes Substituted aromatic group (Toluene, Phenols, Anisole). Ethers Thioethers Amines

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FACTORS AFFECTING OXIDATION PROCESS1) Oxygen concentration

2) Light

3) Heavy metals particularly those having two or more valence state

4) Hydrogen & Hydroxyl Ion

5) Temperature

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PREVENTION OF OXIDATION

1) Reducing oxygen content2) Storage in a dark and cool condition3) Addition of chelating agent (Eg. EDTA, Citric acid, Tartaric

acid)4) Adjustment of pH5) Changing solvent (Eg. Aldehydes, ethers, Ketones, may

influence free radical reaction)6) Addition of an antioxidant.

a) Reducing agentb) Chain inhibitors of radical induced

decomposition

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HYDROLYSIS

It involves nucleophilic attack of liable group Eg. Lactum > Ester > Amide > Imide When this attack is by a solvent other than water than it is known as solvolysis It generally follows 2nd order kinetics as there are two reacting species, water

and API. In aqueous solution, water is in excess, the reaction is 1st orde.

Conditions that catalysis the breakdown

• Presence of hydroxil ion

• Presence of hydride ion

• Presence of divalent ion

• Heat

• Light

• Ionic hydrolysis

• Solution polarity and ionic strength

• High drug concentration

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PREVENTION OF HYDROLYSIS pH adjustment Formulate the drug solution close to its pH of optimum sability. Addition of water miscible solvent in formulation Optimum buffer concentration Addition of surfactant Nonionic, cationic, and anionic surfactant stabilizes the drug

against base catalysis

Salts and Esters Eg.Phosphate esters of clindamycine The solubility of p’ceuticals undergoing ester hydrolysis can be

reduced by forming less soluble salts. By use of complexing agent

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PHOTOLYSIS

Mechanism of decomposition Electronic configuration of drug overlaps with spectrum of

sunlight or any artificial light & thereby energy is absorbrd by electron and it goes to the excited state.

They are unstable and releases the acquired energy and come to the ground state and decompose the drug

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PHOTODECOMPOSITION PATHWAY

N-Dealkylation

Eg. Diphenylhydramine , Chloroquine, Methotrexate Dehalogination

Eg. Chlorpropamide, Furosemide Dehydrogenation of Ca++channel blocker

Eg. Solution of Nifedipine

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Oxidation

Eg. Chlorpromazine & other Phenothiazines give N- & S- oxides in the presence of sunlight

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PREVENTION OF PHOTODECOMPOSITION:- Suitable packing.

Eg. Yellow-green glass gives the best protection in U.V. region while Amber confers considerable protection against U.V. radiation but little from I.R.

Protection of drug from light

Eg. Nifedipine is manufactured under Na light. Avoiding sunbath.

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RACEMIZATION

The interconversion from one isomer to another can lead to different P'cokinetic properties (ADME) as well as different P'cological & toxicological effect.

Eg. L-epinephrine is 15 to 20 times more active than d-form, while activity of racemic mixture is just one half of the L-form.

It depends on temperature, solvent, catalyst & presence or absence of light.

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POLYMERIZATION

It is a continuous reaction between molecules. More than one monomer reacts to form a polymer. Eg. Darkening of glucose solution is attributed to

polymerization of breakdown product [5- (hydroxyl methyl) furfural.

Eg. Shellac on aging undergoes polymerization & hence prolongs disintegration time &dissolution time.

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ISOMERIZATION

It is the process involving change of one structure to another having same empirical formula but different properties in one or more respects.

Its occurrence is rare. Examples:-

Tetracycline & its dvts. can undergo reversible Isomerization at pH range 2-6.

Trans-cis Isomerization of Amphotericin B.

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DECARBOXYLATION

Evolution of C02 gas from -COOH group containing drugs. Eg. Solid PAS undergoes decarboxlation to m- aminophenol &

Carbondioxide.

Enzyme Decomposition Chemical degradation due to enzymes induced by drug results

into decomposition.

Remedy: Use of buccal tab. Use of pro-drug. (L-dopa). Improvement in physicochemical properties has been

achieved by structural optimization or prodrug approach - Enhancement of occular penetration when given orally.(ORAL DRUG DELIVERY SYSTEM)

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REFERENCES:

Pharmaceutics- The science of Dosage Form Design by M. E. Aulton.(2nd edition): pg.113

The Science & Practice of Pharmacy by Remington. (19th edition): 1447

The Theory & Practice of Industrial Pharmacy by Leon Lachman, HerbetA. Lieberman, Joseph L. Kaing. (3rd edition): pg. 171

Pharmaceutical Dosage Forms by Leon Lachman, Herbet A. Lieberman; (Volume I): pg. 1

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THANK YOU

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