Preformulation and Pharmaceutical Analysis PDF

Preformulation: A foundation for dosage form development Vibhuti Agrahari, PhD College of Pharmacy University of Oklahoma  Learning Resources Format of the courses: Lectures and visual aids TEXTBOOK (optional): Pharmaceutical Do...

Preformulation: A foundation for dosage form development Vibhuti Agrahari, PhD College of Pharmacy University of Oklahoma  Learning Resources Format of the courses: Lectures and visual aids TEXTBOOK (optional): Pharmaceutical Dosage Forms and Drug Delivery Systems. Howard C. Ansel, Lloyd V. Allen, and Nicholas G. Edition 10th, 2013, Lippincott Williams & Wilkins. Applied Pharmaceutics in Contemporary Compounding, Robert P. Shrewsbury, Edition 3rd, Morton publishing. Martin’s Physical Pharmacy and Pharmaceutical Sciences, Sinko, P.J., 6th (ISBN-13: 978-0781797665) or 7th (ISBN-13: 978-1451191455) Edition, 2006 or 2010, Lippincott Williams & Wilkins. Trevor M. Jones, CHAPTER 1:Preformulation Studies , in Pharmaceutical Formulation: The Science and Technology of Dosage Forms, 2018, pp. 1-41 DOI: 10.1039/9781782620402-00001 eISBN: 978-1-78262-040-2; From Book Series: Drug Discovery ICH Guidelines: https://www.ich.org/page/quality-guidelines 2  Learning Objective 1.Define preformulation 2.What are pre-formulation parameters ▪ Physical Characteristics ▪ Chemical Characteristics 3. Discuss stability studies and different factors affecting it 4. Why stability testing: ICH guidelines 5. What are force degradation studies ? 6. Describe different testing conditions: Hydrolysis, Oxidation, Thermal, Photolytic 7. Different mechanism of the drug-excipient interaction ▪ Physical drug-excipient interactions ▪ Chemical drug-excipient interactions ▪ Physiological/Biopharmaceutical drug-excipient interactions 8. Explain chemical instability: Hydrolysis, Oxidation, Photolysis, Racemization, Polymerization 9. What are various analytical testing methods for pharmaceuticals ▪ Physical testing methods ▪ Methods that interact with electromagnetic radiation ▪ Separation techniques: chromatography ▪ Immunoassay methods 10. Chromatography ▪ Why chromatography ▪ Principle and type of chromatography ▪ What is stationary phase, mobile phase, eluent, chromatogram and chromatography method.  Preformulation: Definition Preformulation investigations are designed to collect necessary data especially; ✓ physicochemical properties of drug substances ✓ excipients ✓ packaging materials Useful in developing stable and bioavailable dosage forms that can be mass produced.  Preformulation Parameters A.PHYSICAL CHARACTERISTICS 3) Solubility analysis (Fall Semester) a) Partition co-efficient 1) Organoleptic properties b) Solubilization Description of the drug substance based on c) Dissolution (Covered by Dr. Garcia- color, odor and taste. Contreras –Spring) Color Odor Taste White Pungent Acidic Off-white Fruity Bitter 4) Stability analysis (Fall Semester) Drug-excipients compatibility Yellow Odorless Sweet B. CHEMICAL CHARACTERISTICS 1) Hydrolysis 2) Bulk characteristics a) Solid state characteristics 2) Oxidation b) Flow properties c) Crystalline 3) Photolysis d) Densities 4) Racemization e) Substance under atmosphere/ Humidity 5) Polymerization Bulk Characteristics a) Solid state characteristics: Example (Suspensions dosage forms); Particle size can influence variety of factors: Suspendability Uniform distribution Lack of grittiness Case: Ocular suspension: https://www.besivance.com/ b) Flow properties: Powders may be free flowing or cohesive (non free flowing). Case: Drug is identified as a "poorly flowable,” (at the pre-formulation stage) the problem can be solved by selecting appropriate excipients; example: glidant. c) Crystallinity: Crystalline compounds are characterized by repetitious spacing of constituent atom or molecule in three- dimensional array. In amorphous form atom or molecule are randomly placed. Density: The ratio of mass to volume is known as density D= m/v Types of density: (a) Bulk density: It is obtained by measuring the volume of known mass of powder that passed through the screen. (b) True density: Actual density of the solid material. True density  Substance under atmosphere/Humidity – Varieties of excipients Many drug substances exhibit a tendency to absorb moisture. These are classified as; Deliquescent: A substance which absorb sufficient moisture from the atmosphere to dissolve itself. High affinity to water and may turned to solution. Desiccants. NaOH (Sodium hydroxide) Efflorescent: A substance which loses water to form a lower hydrate or become anhydrous) from hydrated salts. Na2CO3 10H2O Hygroscopic: A substance that exist in a dynamic equilibrium with water. Humectants, Glycerin. Hygroscopy is the phenomenon of attracting and holding water molecules via either absorption or adsorption from the surrounding environment, which is usually at normal or room temperature. desiccator  Practice question 1 Q. A substance which absorb sufficient moisture from the atmosphere to dissolve itself. High affinity to water and may turned to solution. A) Deliquescent B) Hygroscopic C) Efflorescent D) Effervescent  Stability analysis WHY?? To generate useful information on how environmental factors such as temperature, humidity, light etc. influence the quality of drug products over time. To establish how physical, chemical and microbiological changes influence the effectiveness, safety and stability of the final drug product. To recommend storage conditions and shelf life of drug products. What are changes? Physical changes – changes in the physical appearance clarity and color of solution, crystal modification and particle size etc. Chemical changes – increased degradation and decrease drug/API (Active Pharmaceutical Ingredient) concentration Microbial changes – increased microbial load/microbial contamination. Stability Studies are preformed on: Drug Substances (DS): Unformulated drug substance/API Drug Products (DP): The dosage form in the final immediate packaging intended for marketing.  What or Who is ICH? ICH stands for International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human use Objectives of ICH ICH is a joint initiative involving both regulators and industry as equal partners in the scientific and technical discussions of the testing procedures which are required to the safety, quality and efficacy of medicine. Rational use of human, animal and other resources, availability of new medicines while maintaining safeguards (safety, quality, efficacy) and regulatory obligations to protect public health.  Example: ICH Guidelines: Forced degradation studies ✓ An Approach to analyses the stability of drug samples. ✓ Stability of molecule information provides the data for selecting proper formulation, package, proper storage conditions and shelf life. Different conditions; Hydrolytic : Acidic & Basic conditions Oxidation: Hydrogen peroxide Thermal: Dry heat exposure Photolytic condition: UV radiation exposure The ICH guidelines that are applicable to forced degradation studies are: ICH Q1A – Stability Testing of New Drug Substances and Products Not for ICH Q1B – Photostability Testing of New Drug Substances and Products exam ICH Q2B – Validation of Analytical Procedures: Methodology https://www.ich.org/fileadmin/Public_Web.../ICH.../Guidelines/.../Q1B_Guideline.pdf Flow chart for performing stress studies for degradation under oxidative conditions Climatic Zones / Storage conditions (Fall Semester)  Practice question 2 Q. Which of the following conditions used for the forced degradation studies to study stability of drug degradation? A) pH B) Heat C) Hydrogen peroxide D) UV-light E) All conditions A, B, C, D Pre-formulation Studies: Drug-Excipient Compatibility Studies *Excipients are pharmacologically inert substances; but they can undergo chemical reactions and physical interactions with drug substances under environmental conditions. Mechanism of Drug-Excipient(s) interactions: a. Physical drug-excipient interactions b. Chemical drug-excipient interactions Formulation undergoes a chemical reaction in which the constituent are rearranged via bond breakage and bond formation to produce an unstable chemical entity. Chemical interactions can be in the form of hydrolysis, oxidation, photolysis, racemization, polymerization, etc., c. Physiological/Biopharmaceutical drug-excipient interactions *Excipients: [Fall Semester]: Ideally, an excipient is pharmacologically inactive, non- toxic, and does not interact with the active ingredients or other excipients.  Physical Drug-Excipient Interactions Improves bioavailability of sparingly water-soluble drugs: Bioavailability can be enhanced using complexing agents e.g., complexation of drug substance with cyclodextrin increases the rate and extent of drug dissolution which in turn increases the bioavailability of the drug substance. Example: Piroxicam (NSAIDs) DOI: 10.1517/17425247.2.1.335 Mechanisms of Degradation 1) Hydrolysis 2) Oxidation 3) Photolysis 4) Racemization 5) Polymerization Hydrolysis is a process in which (drug) molecules interact with water molecules to yield breakdown products. For example, aspirin, or acetylsalicylic acid, combines with a water molecule and hydrolyzes into one molecule of salicylic acid and one molecule of acetic acid. Hydrolysis can be prevented by reducing or replacing water with glycerin, propylene glycol or ethanol for liquid formulation. Vegetable oil is used for injectables.  Oxidation Oxidation is a loss of electrons from an atom or a molecule or loss of hydrogen (dehydrogenation) from a molecule. Addition of antioxidant: These chemicals have electrons or available hydrogen atoms that are preferentially oxidized. Aqueous formulation: Sodium thiosulfate Non-aqueous formulation: Butylated Hydroxy Toluene (BHT). Addition of chelating agent: It forms complex with trace amount of heavy metal ion & inactivate their catalyzing activity. E.g. EDTA  Photolysis Catalyzed by normal light or sunlight Mechanism: Electronic configuration of drug overlaps with the spectrum of sunlight or any artificial light where energy is absorbed by the electron resulting in excitation followed by release of the acquired energy and return to the ground state by decomposing the drug. Prevention: Use packaging material like amber glass, opaque containers, aluminum foil Example: Nifedipine doi: 10.1248/ Polymerization It is a continuous reaction between two or more identical molecules. More than one monomer reacts to form a polymer. Eg. Polymerization of formaldehyde (HCHO) to paraformaldehyde (CH2O)n which causes the solution cloudy. Racemization The interconversion from one isomer to another can lead to different pharmacokinetic properties (ADME) as well as different pharmacological & toxicological effect. Example of drugs: Levocetirizine Cetirizine (Zyrtec) is a potent and long-acting second-generation histamine H1- receptor antagonist for the treatment of allergic disease, such as allergic rhinitis, in adult and child. It is a racemic mixture of levocetirizine (Xyzal; third generation) and dextrocetirizine. https://pubmed.ncbi.nlm.nih.gov/19175892/ Physiological/Biopharmaceutical Drug-excipient Interactions Premature breakdown of enteric coat Enteric coating polymers e.g., cellulose acetate phthalate dissolve prematurely in the stomach in the presence of antacids drugs. This results in premature release of API in stomach itself. Interactions due to adjunct therapy Biopharmaceutical incompatibility is the interaction between tetracycline antibiotics and antacids containing aluminum, calcium, magnesium and zinc ions. The tetracycline antibiotics chelates with these metallic ions to form complexes which are poorly absorbed and have reduced antibacterial effects.  Practice question 3 A process in which drug molecules (Example; aspirin) interact with water molecules to yield breakdown products is called as A) Hydrolysis B) Polymerization C) Oxidation D) Racemization  Analytical Chemistry: Science of Chemical Measurements Qualitative analysis is what. Quantitative analysis is how much. Areas of chemical analysis - characterization of a sample material ▪ Detection: Does the sample contain substance X? ▪ Identification: What is the identity of the substance in the sample? ▪ Quantitation: How much of substance X is in the sample? ▪ Separation: How can the species of interest be separated from the sample matrix for better quantitation and identification?  Analytical Testing Methods for Pharmaceuticals Generally divided into; ✓ Physical testing methods : Melting point, boiling point, color change ✓ Methods that interact with electromagnetic radiation ✓ Separation techniques: chromatography ✓ Immunoassay methods Immunoassay: used to test for the presence of a specific antibody or a specific antigen in a blood or body fluid sample ❑ Radio-immuno-assay (RIA) ❑ Enzyme linked immunosorbent assay (ELISA)  Interaction of electromagnetic radiation Study of the interaction between matter and electromagnetic radiation: Spectroscopy ❑ Ultraviolet/Visible spectroscopy ❑ Infrared spectroscopy ❑ X-ray spectroscopy ❑ Flame emission and Atomic absorption spectroscopy ❑ Mass spectrometry  Interaction of electromagnetic radiation ❑ UV-Visible spectroscopy: Determine the concentration of an analyte (Example; Ibuprofen, Naproxen) in solution ❑ Infrared spectroscopy: Determine the functional groups (NHs ❑ X-ray diffraction spectroscopy: used for identification of a crystalline material and can provide information on unit cell dimensions ❑ Flame emission and Atomic absorption spectroscopy: analytical technique that measures the concentrations of an elements ❑ Mass spectrometry (MS) is an analytical technique that ionizes chemical species and measures the mass within a sample  Practice question 4 Q. The analytical technique that ionizes chemical species and measures the mass within a sample A) Flame emission spectroscopy B) Immunoassay C) Chromatography D) Mass spectrometry E) Atomic absorption spectroscopy  Practice question 5 Q. X ray diffraction pattern indicates … A. Solubility B. Permeability C. Crystallinity D. Functional groups  Chromatography: Separation techniques Why? Used to separate mixtures of substances into their components. The goal of chromatography is to identify, and/or quantify, purify the components of complex mixtures. Chromatography enables the separation of compounds in a mixture by dissolving the mixture in a mobile phase (solvent or mixture of solvent) and passing this mixture over a stationary phase (adsorbent). Molecules (For example; API example Valsartan) that interact strongly with the stationary phase (or have a greater affinity for the stationary phase than the mobile phase) migrate through the resin/silica slowly, whereas molecules that interact weakly with the resin/silica move through it quickly. Thin layer Column  Chromatography: Separation techniques Principle: Mixture is dissolved in a fluid called the mobile phase, which carries it through a structure holding another material called the stationary phase. Various constituents of the mixture travel at different speeds, causing them to separate. Stationary phase: In analytical chemistry, the stationary phase is a solid. through which the mobile phase passes. The most common stationary phase for column chromatography is silica gel. Polar in nature. Mobile phase: The mobile phase, also known as eluent, is a solvent or a mixture of solvents that is used to move compounds through the column. Solvents used as mobile phases based on their polarity include ethanol, acetone, water, acetonitrile and others. Elution: The process of extracting one material from another in analytical and organic chemistry by washing with a solvent is said to be elution. The process of elution is based on the differential adsorption of a substance by the adsorbent. Practice question 6 1.The component with higher speed is _____ 2.The most readily adsorbed component is ______ 3.Arrange the components in the order in which they will elute.  Chromatography: Separation techniques Chromatography Method: Chromatography is a laboratory technique for separating a mixture by passing it through a medium in which the mixture’s components move at different rates and thus separate. As we can see, no chemical reactions are taking place; instead, their separation is caused by differences in rates and mobility. As a result, chromatography is a physical process. Chromatogram: A chromatogram is a visible record (such as a graph) demonstrating the outcome of separating the components of a mixture using chromatography. HPLC Types of chromatography: ❑ HPLC (High performance liquid chromatography) - Lab 12: Quality Control - HPLC ❑ GC (Gas chromatography) ❑ Column chromatography ❑ Thin layer chromatography ❑ Paper chromatography  Practice question 7, 8, and 9 7. Chromatography is a A. Chemical method B. Biochemical method C. Physical method D. Novel Method 8. Eluting power is related to the A. Solvent B. Solute C. Both solute and solvent D. Solution 9. Which substances elute first? Is it polar or nonpolar? Answer: Hint: : With less adsorption, the component elutes first Not for exam  Case Study on Valsartan – FYI Chromatography and stability studies  Case Study on Valsartan – FYI Chromatography and stability studies  Learning Objective 1.Define preformulation 2.What are pre-formulation parameters ▪ Physical Characteristics ▪ Chemical Characteristics 3. Discuss stability studies and different factors affecting it 4. Why stability testing: ICH guidelines 5. What are force degradation studies ? 6. Describe different testing conditions: Hydrolysis, Oxidation, Thermal, Photolytic 7. Different mechanism of the drug-excipient interaction ▪ Physical drug-excipient interactions ▪ Chemical drug-excipient interactions ▪ Physiological/Biopharmaceutical drug-excipient interactions 8. Explain chemical instability: Hydrolysis, Oxidation, Photolysis, Racemization, Polymerization 9. What are various analytical testing methods for pharmaceuticals ▪ Physical testing methods ▪ Methods that interact with electromagnetic radiation ▪ Separation techniques: chromatography ▪ Immunoassay methods 10. Chromatography ▪ Why chromatography ▪ Principle and type of chromatography ▪ What is stationary phase, mobile phase, eluent, chromatogram and chromatography method.