SEMINAR ON PHYSIOCHEMICAL FACTORS INFLUENCING FORMULATION PRESENTED BY:- VBM ROLL :- 12 YEAR-2010-2011
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.
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.
1) Crystallinity and Polymorphism
3) Particle Size & Surface Area
4) Flow properties & Bulk density
6) Drug- Excipient Compatibility
B. SOLUBILITY ANALYSIS 1) Ionization constant 2) Solubilization. 3) Partition Coefficient 4) Thermal effect 5) Common ion effect. 6) Dissolution. C. STABILITY ANALYSIS 1) Solid State Stability. 2) Solution State Stability
II. CHEMICAL CHARACTERISTIC
8) Enzyme Decomposition.
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
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
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
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.
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
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.
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
METHODS TO DETERMINE pKa
Dissolution rate method
Liquid liquid partition method
Many different approaches have been developed to improve drug solubility
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
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.
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.
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
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
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 5 0 C, 25 0 C, 37 0 C, & 50 0 C.
Important: Determination of temp effect on solubility helps in predicting storage condition & dosage form designing
COMMO N ION EFFECT:-
To identify a common ion interaction IDR of HCL salt should be compared between
Water and water containing 1.2% W/V NaCL
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
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 systemic circulation Dissolution Absorption Kd Ka When Kd<<<<<Ka absorption is dissolution rate limited
Dissolution rate can affect:-
Onset of action
Intensity of action
Duration of response
Control the overall bioavaibality of drug form
Development of a drug substance into a suitable dosage form repairs the preformulation stability studies as:
 Solid state stability
 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
Technique for solid state stability studies:
Solid state NMR Spectroscopy (SSNMR)
Powder x-ray diffraction (PXRD)
Fourier transform IR (FTIR)
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
-Ionic strength -Coosolvent
If the result of this solution stability studies dictate the compound as sufficiently stable, liquid formulations can be developed.
It is very common pathway for drug degradation in both liquid and solid formulation
Oxidation occurs in two ways
Free radical oxidation
Functional group having high susceptibility towards oxidation:-
Substituted aromatic group (Toluene, Phenols, Anisole).
FACTORS AFFECTING OXIDATION PROCESS
Heavy metals particularly those having two or more valence state
Hydrogen & Hydroxyl Ion
PREVENTION OF OXIDATION
Reducing oxygen content
Storage in a dark and cool condition
Addition of chelating agent (Eg. EDTA, Citric acid, Tartaric acid)