We have dealt with the bulk characterization in our last blog and now let us discuss the other principle areas that are involved in the preformulation studies like solubility and stability analysis.
First of all Let us go through the solubility analysis.
The commonly Used solvent for the determination of the solubility are 0.9% NaCl solution, 0.01MHCl, 0.1M NaOH etc. We can determine the drug concentration with the help of HPLC, UV-Spectroscopy, Fluorescence spectroscopy and gas chromatography. The pH, temperature, ionic strength and buffer concentration mainly affect the solubility of the drug.
When we administer either a weakly basic or acidic drug, it will undergo ionization in GI fluids. But generally the unionized drug molecules are better absorbed than the ionized drug molecules.
The ionized and unionized drug concentration at a particular pH can be determined by using Handerson-Hasselbach equation as given below.
pH = pKa + log [ionized form]/ [unionized form] (for acidic drug) and
pH= pKa + log [un-ionized]/ [ionized form] (for basic drug).
For the aqueous dilute solution, the UV or visible spectroscopy is the best method to determine pKa at various pH.
For those compounds which are having the pKa value in between 3 to 10, we can determine by using potentiometric method.
The amount of the heat that may be either released or absorbed during the dissolution of 1 mole of solute in a large amount of solvent is represented as heat of solution (rHs). In case of the endothermic reactions, which is more frequent in solubilization, it is +ve. Temperature increase enhances the solubility.
For those drug candidates which are having poor aqueous solubility, preformulation studies will highlight the conditions which increase the solubility.
The solubility can be increased by
-using micellar solutions
-Forming complexes etc.
It is given by formula,
Ko/w = [Corganic/ C aqueous] (at equillibrium)
More the K o/w valuerepresents that the drug has more ability to cross lipid cell membrane.
Chemical form, crystal habit, particle size, surface area, wetting, solubility are the properties that widely influence the dissolution of the drug.
Dissolution rate of a drug substance as represented by modified Noyes-Whitney equation is given as follows (where surface area remains constant during disintegration)
dC/dt = DA/hV (Cs-C)
D = diffusion coefficient in the dissolution medium
H = thickness
A = surface area
V = volume
Cs = concentration of the drug at saturated solution
C = concentration at particular time t
Stability in toxicology formulations:
A new drug can be given to the animals through:
-by mixing it with the food
-in the form Of solution using water as a vehicle
-in the form of suspension using water as a vehicle
The food that the animal take can decrease the stability and hence these analysis are done at laboratory condition along with the food. When the drug is administered in the form of the solution or suspension,then the chemical stability at various temperatures and pH has to be inspected. As usual in the case of suspensions, shake well to get uniformity.
Objective: This is done in order to find out the desired conditions to make the drug solution stable.
Stability of A new drug may depend on:
(i) pH (ii) ionic strength (iii) co-solvent
(iv) light (v) temperature (vi) oxygen.
pH: the pH stability is done in the conditions like 0.1N HCl, 0.1N NaOH and water at 90oC.
-the drug is dissolved in the various buffers made of water having different pH values but with constant levels of drug concentration, co-solvent and ionic strength. Now the plots are drawn between the rate constants (k) and pH.
Ionic strength(u): it is given by the formula,
u=1/2 E mizi2
mi -concentration of ion
Co-Solvents: A plot is drawn between the various concentrations of the co-solvent and k. then it is extrapolated to the 0% co-solvent to produce the actual k value (i.e. in pure solvent).
Light: the stability tests are carried out by keeping the drug solution in the clear ampoules, amber colored glasses or yellow green colored glasses etc.
Temperature: the rate constant will change with temperature and it is given by the Arrhenius equation.
Solid state stability:
The main motto of conducting these studies is to find out the suitable storage conditions in the solid form and also to determine the excipients for preparation of the dosage form.
The formation of the decay products is generally observed as the reactions in the solid state are very slow.
-DSC Or IR spectroscopy can be used to study polymorphic changes.
-Surface reflectance can be used to determine the surface Discoloration.
-by using the TLC or UV/Visible spectroscopy we can study the mechanism of degradation.
The theory and practice of Industrial Pharmacy by Leon Lachman and Herbert A. Liberman, special Indian edition 2009, CBS publishers, page no 184 to 194.
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