Factors Affecting Drug Stability Lecture Notes PDF

# PHARMACEUTICAL DOSAGE FORMS III - PPC 301 ## FALL 2024-2025 ### Lecture (10) ### Factors affecting drug stability Prepared by D. Basant A. Abou-Taleb, M.sc., PHD Lecturer of Pharmaceutics & Ph. Technology Department Pharos University of Alexandria (PUA) # Factors influencing the rate of decomposi...

# PHARMACEUTICAL DOSAGE FORMS III - PPC 301 ## FALL 2024-2025 ### Lecture (10) ### Factors affecting drug stability Prepared by D. Basant A. Abou-Taleb, M.sc., PHD Lecturer of Pharmaceutics & Ph. Technology Department Pharos University of Alexandria (PUA) # Factors influencing the rate of decomposition (Drug Stability) ## I. Storage conditions- related factors 1. Temperature 2. Humidity 3. Oxygen 4. Light ## II. Solution related factors 1. pH ( buffers) 2. Catalyst 3. Dielectric constant = polarity (solvent selection) 4. Surfactants 5. Ionic strength of ( solvent, electrolytes) ### Solution related factors ### 1. pH ( addition of buffers) - The hydrolysis is affected by the pH of the drug solution #### Hydrolysis can be catalyzed by: | | | | | :--------------------------------- | :--------------------------------- | :------------------------------------------------------ | | **H+** | **OH-** | **Other acidic or basic species in the used buffer.** | | **Specific acid catalysis** | **Specific base catalysis** | **(Neither H+ nor OH-)** | | **General acid-base catalysis** | | | | i.e. the reaction rate is much faster in acidic medium> neutral medium | i.e. the reaction rate is much faster in basic medium> neutral medium | i.e. The reaction rate is much faster in certain buffers> non- buffered solution <br> E.g. catalysis of glucose decomposition by sodium acetate buffer | - Now if you need to add a buffer (i.e. adjust the pH of the drug solution), How would you know the **optimum pH for drug stability**? - During the development of the drug formulation, several drug solutions are prepared; each adjusted at a different pH. - The decomposition reaction rate is evaluated at each of these pH values. - A pH-rate profile is plotted. Here you can know the optimum pH at which the solution is at its maximum stability. ### Example : - Pre-formulation studies determine the pH of maximum stability which may not be suitable for drug solubility or therapeutic activity. - Ex. The weak basic drugs as Pilocarpine, Atropine and Physostigmine eye drops. - They are most stable in acidic solution, but most active as free base (be less soluble). ### Solution related factors ### 2. Catalyst - Catalysis : The rate of a reaction is frequently influenced by the presence of a catalyst. - Catalyst: is a substance that accelerates the rate of chemical reaction without being changed or consumed chemically. - Catalysis is considered to operate by combination with the reactant (substrate) and forms an intermediate known as a complex, which then decomposes to regenerate the catalyst and yield the products. <br> Catalyst + Reactant (Substrate) - Catalyst-reactant complex - Decomposes - Catalyst + Product - Catalytic action may be homogeneous or heterogeneous and may occur in either the gaseous or the liquid state. #### 1. Homogeneous catalysis: occurs when the catalyst and the reactants are in the same phase. #### 2. Heterogeneous catalysis: occurs when the catalyst and the reactants from separate phases in the mixture involves the use of solid catalysts placed in a liquid reaction mixture. ### Solution related factors ### 2. Catalyst #### Specific acid-base catalysis: - As the reaction of (drug decomposition) affected only by the concentration of H+ (hydrogen) or OH- (hydroxyl ions) (specific to acid or base concentration added) and divided into: - Specific acid catalysis - Specific base catalysis #### General acid-base catalysis: - As the reaction rate is not only affected by the pH of the medium but also affected by the type of the weak acid used (Not specific to the acid or base concentration) - Example of catalyst: The catalyst may be a finely divided solid such as platinum or it may be the walls of the container. ### Solution related factors ### 3. Effect of Solvent (Dielectric constant = polarity) - The solvent effect on the rate on the reaction depends on: - The polarity of solvent - The electrical charge of the reactants (drug ) - In case of chemical reaction with neutral reactants, the solvent polarity couldn't affect the reaction rate. ### Solution related factors ### 4. Effect of Surfactant - It has been found that entrapping the drug into micelles can actually improve the drug stability against hydrolysis - The surfactant in micellar form may affect hydrolysis rate of drugs according to the extent of solubilization - Ko = K_m f_m + K_w f_w. - K_m (micellar constant) value: is dependent on the drug location within the micelle, i.e. non-polar drugs are solubilized within the lipophilic core (more protected), while those located close to micellar surface are less protected. ### Solution related factors ### 4. Effect of Surfactant - This protection depends on: - Whether the drug is entrapped in the lipophilic micellar core or near to the surface. Which one would offer a higher stability? - Lipophilic micellar core - The ionic nature of the SAA also matters - E.g. if the drug is hydrolyzed by base-catalyzed hydrolysis (i.e. by OH-), and you used an anionic SAA, a repulsion will occur between the micelles & the interacting anion. - However, if you selected a cationic SAA in this example, it will actually increase the drug decomposition & decrease stability. ### Solution related factors ### 5. Ionic strength of solvent (μ) - Ionic strength of a solution means measuring of the concentration of ions in the solution. - Effect of ionic strength is meaning addition of inert electrolyte to aqueous solution of drug_exerting direct effect_on stability even there is no chemical interaction between this electrolyte and the drug. - Such effect is known as primary salt effect A^ZA + B^ZB → (A-----B)^(ZA+ZB) → products - $μ$ = 0.5 [ ε m_i z_i²] - Where; - μ=ionic strength - m_i=molar concentration - z_i=number of charge of ions ### Solution related factors ### 5. Ionic strength of solvent (μ) - In a reaction between ions, the reactants A and B have charges ZA and ZB, respectively, and the activated complex (A-----B)* has a charge (ZA + ZB) This reaction can be expressed as: A^ZA + B^ZB → (A-----B)^(ZA+ZB) → products - The rate of this reaction will depends on the ionic strength and the rate equation can be expressed as follow: - Where; - K= specific rate constant. - μ= the ionic strength - k_o= is the rate constant at infinite dilution of solution where μ = zero. - If one of the reactants is neutral (i.e. ZA ZB =0) and the reaction rate is independent on ionic strength - log k = log k_o + 1.02Z_AZ_B√μ - log k - k_o - √μ - slope = {1.02 Z_A Z_B } # Mechanisms of drug incompatibilities ### Chemical Incompatibilities - They are chemical interactions between two or more drug components in the same dosage form, or between drug and pharmaceutical adjuvant. - Many pharmaceutical incompatibilities are the result of reactions involving amine functional group. # Types of in vitro interactions 1. Drug-Drug interaction - The inactivation of cationic aminoglycoside antibiotics as kanamycin, gentamicin by anionic penecillins in IV admixture. - Anionic heparin as and aminoglycoside antibiotics - Due to formation of inactive complex 2. Drug-Excipient interaction - Epinephrine sulfate with steroid sodium phosphate - Eye drops containing polymyxin B sulfate and dexamethasone sodium phosphate - Cause precipitation 3. Drug- Packaging material interaction 4. Others # Types of in vitro interactions 1. Drug- Drug interaction - Aminophylline & glucose forms Schiff's base formation (yellow ppt) - Phenolic (phenobarbitone) & Acidic drug (Aspirin) + Tween 80 (CH2-O-CH2) interact by H-bonding leads to ester formation # Types of in vitro interactions 1. Drug- Excipient interaction - Diphenhydramine HCI + Anionic surfactant (Ex: SLS, Na stearate) - Phenobarbitone Na + Cationic surfactant (Ex: Cetrimide) # Thank you - Dr. Basant Abou-Taleb