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- 1. Pre Formulation and Stability Analysis PRESENTEDBY-NITIN GARG GARGI VERMA CLASS- MBA 1ST YEAR SECTORAL –PHARMACEUTICAL MANAGEMENT ROLL NO- 27182 and 27183
- 2. Table of Content •Introduction to Pre formulation • Historical Context and Evolution of Pre formulation • Fundamental Objectives of Pre formulation • Physical Characterization and Chemical Stability Aspects • Biopharmaceutical Properties and Excipient Compatibility Studies • Advanced Pre formulation Techniques and its Integration with Formulation Development • Regulatory Considerations and Future Directions of Pre formulation • Stability Analysis in Industrial Pharmacy • Purpose and types of Stability Analysis in Industrial Pharmacy • Factors Influencing Drug Stability: • Key Elements to Design Stability Studies
- 3. Introduction to Preformulation Pre formulation is the initial and critical phase in drug development where scientists study the physical, chemical, and mechanical properties of a drug substance. This process helps determine how the drug will behave in different formulations and ensures optimal stability, efficacy, and bioavailability. Think of pre formulation as a "background check" for a new drug molecule before it enters full-scale formulation development. It helps identify potential challenges early, saving time, money, and effort in later stages.
- 4. Historical Context andEvolution of Pre formulation Let's take a look at how pre formulation has progressed over time. 1. Early Drug Preparation (Ancient to 19th Century) • In ancient civilizations (Egyptian, Greek, Chinese, and Indian), medicines were formulated based on empirical knowledge, often using natural substances like herbs, minerals, and animal extracts. • There was little scientific understanding of drug stability, solubility, or bioavailability. Instead, trial-and-error methods were used to determine the best way to administer medications.
- 5. • During theRenaissance and early modern periods, alchemists and apothecaries started refining drug preparations, but there was still no formalized approach to studying drug properties before formulation. 2. Rise of Pharmaceutical Sciences (Late 19th to Early 20th Century) • With the advent of organic chemistry and microbiology, scientists began studying drug compounds more systematically. • Early research focused on basic physicochemical properties, such as melting points, solubility, and chemical reactivity. • The rise of industrial-scale drug manufacturing led to the need for better quality control and reproducibility in drug formulations. 3. Birth of Pre formulation as a Formal Discipline (Mid-20th Century)
- 6. • The 1950sand 1970s saw major advancements in drug development due to improved analytical techniques like chromatography and spectroscopy. • Scientists realized that understanding a drug’s physicochemical, mechanical, and biopharmaceutical properties before formulation was crucial for successful drug development. • Pharmaceutical companies began establishing pre formulation as a distinct phase in drug development, focusing on solid-state properties, solubility enhancement, and stability testing. 4. Modern Pre formulation Science (Late 20th Century to Present) • With the advent of computational chemistry, molecular modeling, and high-throughout screening, predictive pre formulation studies have become more efficient.
- 7. • Advanced techniquessuch as differential scanning calorimetry (DSC), X-ray diffraction (XRD), and nuclear magnetic resonance (NMR) are now used to characterize drug substances. • The focus has shifted toward developing targeted drug delivery systems, improving bioavailability, and designing formulations for personalized medicine. • Regulatory agencies (FDA, EMA, etc.) now emphasize pre formulation data in new drug applications to ensure safety and efficacy
- 8. Fundamental Objectives ofPre formulation Pre formulation serves as the foundation for successful drug formulation by systematically studying the physical, chemical, and biological properties of a drug candidate. The main objectives of pre formulation include: 1. Understanding Physicochemical Properties • Solubility & Dissolution Rate: Determines how easily the drug dissolves in biological fluids, affecting absorption and bioavailability. • Particle Size & Shape: Influences drug flow properties, dissolution rate, and stability. • Polymorphism: Identifies different crystalline forms, which can impact solubility, stability, and therapeutic effectiveness.
- 9. • Hygroscopicity: Assessesthe drug’s ability to absorb moisture, which can affect stability and shelf life. 2. Ensuring Chemical Stability • Evaluates degradation pathways (e.g., hydrolysis, oxidation, photodegradation) to enhance drug stability. • Helps determine suitable storage conditions and packaging materials. • Identifies possible interactions with excipients that could affect drug potency. 3. Enhancing Bioavailability • Determines lipophilicity (log P value), which affects drug absorption and
- 10. • Guides theselection of appropriate formulation strategies (e.g., salt formation, nanoparticles, lipid-based delivery). 4. Selecting Suitable Drug Formulation Approaches • Identifies the best excipients to enhance stability, solubility, and drug release. • Guides the choice of dosage form (tablets, capsules, injections, etc.) based on drug properties. • Helps in designing controlled or targeted drug delivery systems. 5. Supporting Regulatory & Manufacturing Requirements • Provides essential data for regulatory approvals by agencies like the FDA or EMA.
- 11. Physical Characterization andChemical Stability Aspects of Pre formulation Pre formulation studies focus on understanding the physical and chemical properties of a drug substance to ensure successful formulation development. These studies help in optimizing drug stability, bioavailability, and overall performance. 1. Physical Characterization Physical characterization evaluates the solid-state properties of the drug, which impact formulation, processing, and drug performance. Key Physical Properties Studied in Pre formulation: a) Particle Size and Shape d) Crystallinity and Amorphous Nature b) Polymorphism e) Flow Properties and Compressibility
- 12. a) Particle Sizeand Shape • Affects dissolution rate, bioavailability, and uniformity in drug formulations. • Smaller particle sizes generally lead to faster dissolution and absorption. • Larger or irregularly shaped particles may cause flowability issues during manufacturing. b) Polymorphism • Many drugs exist in multiple crystalline forms (polymorphs), which have different solubilities and stabilities. • Some polymorphs may be more bioavailable, while others may be more stable.
- 13. c) Hygroscopicity • Describesthe drug’s tendency to absorb moisture from the environment. • High hygroscopicity can lead to instability, degradation, or poor flow properties. • Measured using techniques like Dynamic Vapor Sorption (DVS). d) Crystallinity and Amorphous Nature • Crystalline drugs have high stability but may have low solubility. • Amorphous drugs dissolve faster but are often less stable. • X-ray Diffraction (XRD) and Differential Scanning Calorimetry (DSC) help characterize these properties.
- 14. e) Flow Propertiesand Compressibility • Important for tablet and capsule formulations. • Poor flow properties can lead to manufacturing issues like inconsistent drug dosing. • Measured using angle of repose, bulk density, and Carr’s index. 2. Chemical Stability Aspects Chemical stability studies help identify degradation pathways and develop strategies to improve drug stability. Key Chemical Stability Parameters in Pre formulation a) Hydrolysis (Water-Induced Degradation) d) Temperature Sensitivity b) Oxidation e) Drug-Excipient Compatibility
- 15. a) Hydrolysis (Water-InducedDegradation) • Common in ester, amide, and lactone drugs (e.g., aspirin). • Affected by humidity, pH, and formulation composition. • Controlled by using anhydrous formulations, pH buffers, or protective coatings. b) Oxidation • Drugs with hydroxyl, thiol, or aromatic amine groups are prone to oxidation. • Oxygen, light, and temperature can lead to degradation in these. c) Photodegradation (Light-Induced Instability) Certain drugs which degrade under UV or visible light exposure in these.
- 16. d) Temperature Sensitivity •High temperatures can lead to chemical degradation or polymorphic transformations. • Conducted using accelerated stability testing (e.g., 40°C and 75% relative humidity for 6 months). e) Drug-Excipient Compatibility • Some excipients may react with the drug, affecting its stability and efficacy. • Studied using Fourier Transform Infrared Spectroscopy (FTIR), Differential Scanning Calorimetry (DSC), and High-Performance Liquid Chromatography (HPLC).
- 17. Biopharmaceutical Properties andExcipient Compatibility Studies Pre formulation is a critical phase in drug development, where the physicochemical and biopharmaceutical properties of a drug candidate are assessed to optimize its formulation. A key aspect of pre formulation is studying the compatibility of the drug with excipients to ensure stability, efficacy, and manufacturability. Biopharmaceutical properties influence drug absorption, distribution, metabolism, and excretion (ADME) Biopharmaceutical Properties in Pre formulation Key properties include:
- 18. 1. Solubility &Dissolution Rate • Determines the drug's bioavailability. • Poorly soluble drugs require solubility enhancement techniques like salt formation, nanotechnology, or amorphous solid dispersions. 2. Permeability • Assesses drug absorption across biological membranes (e.g., intestinal walls). • Evaluated using techniques like Caco-2 cell assays or PAMPA (Parallel Artificial Membrane Permeability Assay). 3. Partition Coefficient (Log P) & Distribution Coefficient (Log D) Log P: Measures lipophilicity (affects drug permeability & distribution) ,While Log D: Adjusted for pH dependency, relevant for ionizable drugs.
- 19. 4. pKa (IonizationConstant) • Influences solubility, permeability, and stability. • Weak acids/bases change ionization based on pH, affecting drug behaviour in the body. 5. Stability & Degradation Kinetics • Evaluates drug stability under different conditions (pH, temperature, light, humidity). • Determines shelf-life and formulation strategies. Excipient Compatibility Studies Excipients are inactive ingredients used to enhance drug formulation. However, drug- excipient interactions can lead to instability, affecting drug performance.
- 20. 1. Importance ofExcipient Compatibility Studies • Prevents degradation due to interactions (e.g., oxidation, hydrolysis). • Ensures uniformity and stability of the final formulation. • Avoids potential toxic byproducts. 2. Methods for Drug-Excipient Compatibility Studies a. Differential Scanning Calorimetry (DSC)-Detects physical or chemical interactions through changes in thermal properties. b. Thermogravimetric Analysis (TGA)-Assesses weight loss under heat, indicating possible degradation.
- 21. c. Fourier-Transform InfraredSpectroscopy (FTIR)-Identifies molecular interactions between drug and excipients (e.g., hydrogen bonding, oxidation). d. X-Ray Powder Diffraction (XRPD)-Determines changes in drug crystallinity due to excipients. e. High-Performance Liquid Chromatography (HPLC)-Quantifies degradation products over time. f. Stress Testing & Forced Degradation Studies-Evaluates compatibility under extreme conditions (pH variations, humidity, UV light).
- 22. Advanced Pre formulationTechniques and its Integration with Formulation Development Pre formulation studies play a crucial role in drug development by assessing the physicochemical, biopharmaceutical, and stability properties of a drug candidate. Advanced pre formulation techniques provide deeper insights into drug behavior, enabling better formulation design, improved drug stability, and enhanced bioavailability. Integrating these techniques with formulation development ensures a rational approach to developing effective and stable pharmaceutical products.
- 23. Advanced Pre formulationTechniques 1. Solid-State Characterization-Understanding the solid-state properties of a drug helps in optimizing its stability and performance in formulation. a. X-Ray Powder Diffraction (XRPD)-Determines the crystallinity of a drug (amorphous vs. crystalline).also helps identify polymorphic forms, which impact solubility and bioavailability. b. Differential Scanning Calorimetry (DSC)-Measures thermal transitions such as melting point, glass transition, and polymorphic transitions and Detects drug-excipient interactions that might cause instability. c. Thermogravimetric Analysis (TGA)-Assesses moisture content and thermal degradation properties and Helps in selecting appropriate drying techniques for formulation. d. Hot-Stage Microscopy (HSM) -Visualizes phase transitions and drug-excipient interactions at elevated temperatures.
- 24. 2. Drug-Excipient CompatibilityStudies Advanced techniques ensure the stability of the drug in the presence of excipients. a. Fourier-Transform Infrared Spectroscopy (FTIR) • Identifies chemical interactions between drug and excipients. • Detects potential degradation mechanisms (oxidation, hydrolysis). b. Isothermal Microcalorimetry (IMC) • Measures heat changes during drug-excipient interaction. • Useful for detecting incompatibility at an early stage. c. High-Performance Liquid Chromatography (HPLC) • Monitors the degradation kinetics of drug-excipient mixtures. • Provides quantitative stability data for formulation design.
- 25. 3. Advanced Solubilityand Permeability Assessment Enhancing drug solubility and permeability is critical for optimizing bioavailability. a. Solubility Enhancement Techniques • pH Adjustment & Salt Formation – Converts poorly soluble drugs into ionizable forms. • Cocrystals & Solid Dispersions – Improves dissolution rate by altering crystalline properties. • Lipid-Based Formulations – Enhances solubility for lipophilic drugs. b. Parallel Artificial Membrane Permeability Assay (PAMPA) • A high-throughput method to predict passive diffusion permeability. • Assists in selecting appropriate permeability enhancers.
- 26. 4. Particle Engineeringfor Improved Drug Performance Particle properties influence drug dissolution, stability, and manufacturability. a. Nanocrystal Technology • Reduces particle size to nanoscale, increasing surface area and solubility. • Improves bioavailability of poorly water-soluble drugs. b. Spray Drying and Freeze Drying • Enhances drug stability and dissolution characteristics. • Useful for preparing amorphous solid dispersions. c. Supercritical Fluid Technology • Produces micronized or nano-sized drug particles with enhanced dissolution rates.
- 27. Integration of AdvancedPre formulation with Formulation Development 1. Rational Excipient Selection • Based on drug solubility, stability, and compatibility data. • Ensures formulation stability and enhances drug performance. 2. Formulation Design Optimization • Utilizing Quality by Design (QbD) principles to systematically study drug-excipient interactions. • Optimizing excipient ratios for better dissolution and controlled release.
- 28. 3. Predictive Modellingand Simulation • In silico modelling predicts drug behaviour in various formulations. • Computational tools simulate drug absorption and pharmacokinetics. 4. Stability and Scale-Up Considerations • Ensuring formulation robustness under different storage and processing conditions. • Using advanced stability-indicating assays to optimize shelf-life.
- 29. Regulatory Considerations andFuture Directions of Pre formulation • Pre formulation plays a vital role in pharmaceutical development by ensuring a drug’s stability, bioavailability, and manufacturability. Regulatory agencies like the FDA (Food and Drug Administration)and ICH (International Council for Harmonization) provide guidelines to ensure pre formulation studies support the safety, efficacy, and quality of drug products. As pharmaceutical science evolves, future directions in pre formulation include AI-driven predictive modeling, nanotechnology, and personalized medicine.
- 30. Regulatory Considerations inPre formulation Regulatory agencies require thorough pre formulation studies to establish the quality, safety, and effectiveness of a drug before moving into clinical trials and commercial production. Key regulatory considerations include: 1. Physicochemical Characterization Compliance • ICH Q6A & Q6B Guidelines require detailed physicochemical characterization of drug substances, including: • Polymorphism (ICH Q6A) • Solubility & Dissolution • pKa, Log P, and Permeability • Hygroscopicity & Stability
- 31. 2. Drug-Excipient CompatibilityStudies • ICH Q8 (Pharmaceutical Development) emphasizes excipient compatibility testing to prevent degradation. • Regulatory authorities require the use of DSC, FTIR, and HPLC to detect incompatibilities. 3. Stability Testing Requirements • ICH Q1A(R2) Stability Testing Guidelines mandate stability testing under different conditions: • Long-term storage (25°C/60% RH) • Accelerated conditions (40°C/75% RH) • Photostability testing (ICH Q1B) • Helps determine shelf life and degradation pathways.
- 32. 4. Biopharmaceutical ClassificationSystem (BCS) & Bioavailability Requirements • The FDA’s BCS-based Biowaiver Guidance categorizes drugs into four classes: • Class I (High solubility, High permeability) – Eligible for biowaiver (no in vivo bioequivalence testing needed). • Class II (Low solubility, High permeability) – Requires solubility enhancement strategies. • Class III (High solubility, Low permeability) – Needs permeability enhancement techniques. • Class IV (Low solubility, Low permeability) – High risk, needs extensive formulation optimization.
- 33. 5. Good ManufacturingPractice (GMP) & Quality by Design (QbD) • ICH Q8-Q11 Guidelines encourage the application of QbD principles to pre formulation: • Identifying Critical Quality Attributes (CQA). • Using Design of Experiments (DoE) for formulation optimization. • Implementing Process Analytical Technology (PAT) to monitor drug properties in real-time. Future Directions in Pre formulation • With advancements in pharmaceutical technology, pre formulation is evolving to include AI-driven predictive analytics, 3D printing,
- 34. 1. AI andMachine Learning in Pre formulation • Predictive modelling for solubility, stability, and excipient compatibility. • AI-assisted molecular docking to design optimal drug formulations. • Automated formulation optimization using big data and algorithms. 2. Nanotechnology for Drug Delivery • Nanocrystals & Liposomes for enhancing bioavailability. • Polymeric Nanoparticles for controlled drug release. • Lipid-based nanoparticles (SLNs & NLCs) for improved drug
- 35. 3. 3D Printingin Drug Formulation • Allows personalized drug formulations with tailored dose, release profile, and combination therapies. • Approved 3D-printed drug: Spritam® (levetiracetam) for epilepsy, with fast disintegration properties. 4. Biologics and Peptide Drug Pre formulation • Pre formulation for monoclonal antibodies (mAbs) focuses on stability & aggregation prevention. • Peptide drugs require advanced techniques like lyophilization and PEGylation for stability.
- 36. 5. Personalized Medicine& Gene Therapy Pre formulation • Advances in genomics and AI-driven drug design are shifting drug development toward patient-specific formulations. • mRNA-based formulations (e.g., COVID-19 vaccines) use lipid nanoparticles for stability and delivery.
- 37. Stability Analysis inIndustrial Pharmacy Stability studies of pharmaceutical products may be expressed as the time during which the pharmaceutical products retain its physical, chemical, microbiological, pharmacokinetic properties and characteristics throughout the shelf life from the time of manufacture. The shelf-life prediction is a major role for the pharmaceutical product development of all the dosage forms and also it is utilized to determine the particular storage conditions and to suggest label instructions.
- 38. Purpose of StabilityAnalysis in Industrial Pharmacy Stability analysis in industrial pharmacy is a critical process used to determine how environmental factors such as temperature, humidity, and light affect the quality, safety, and efficacy of pharmaceutical products over time. The key purposes of stability analysis include : Regulatory Compliance Ensuring Drug Efficacy and Safety Determining Shelf Life and Expiry Date Optimizing Storage Conditions Formulation Development and Optimization
- 39. Types of StabilityStudies in Pharmaceuticals 1. Based on Duration and Storage Conditions Long-Term Stability Studies: Accelerated Stability Studies: Intermediate Stability Testing: These studies involve storing samples of the drug product under recommended storage conditions for an extended period, typically at room temperature. Long-term stability studies help determine the product’s shelf life and expiry date. Samples are subjected to elevated temperature and humidity conditions for a shorter duration to simulate the effects of long-term storage in a shorter time frame. Accelerated studies provide information on potential degradation pathways and help predict shelf life. These studies are conducted at conditions between long-term and accelerated conditions. They provide additional insights into the product’s stability profile, especially when accelerated conditions alone may not be sufficient.
- 40. 2. Based onStress Factors Applied : These studies intentionally subject the drug product to harsh conditions, such as high temperature, humidity, or extreme pH, to accelerate degradation and identify potential degradation products and pathways. Photo-stability studies assess the product’s susceptibility to degradation caused by exposure to light. This is particularly important for products sensitive to light, as degradation due to photolysis can affect product quality. (a) Stress Testing (Forced Degradation Studies): (b) Photostability Testing
- 41. 3. Based onthe Product’s Usage: (a) In-Use Stability Testing (b) Microbiological Stability Testing •Purpose: Determines how long a product remains stable after opening or mixing. •Conditions: Real-world conditions based on storage recommendations. •Duration: Hours to weeks, depending on product type. •Example: Checking how long an insulin pen remains stable after first use. • Purpose: Ensures sterility and prevents microbial contamination in multi-dose formulations. • Conditions: Tested under microbiological challenge conditions. • Example: Testing preservative efficacy in multi-dose eye drops
- 43. Factors Influencing DrugStability: Internal Factors External Factors
- 44. INTERNAL FACTORS: a.) Chemical Structure Thechemical structure of a drug plays a fundamental role in its stability. Certain molecular arrangements are more prone to degradation pathways, such as hydrolysis, oxidation, and photodegradation. Structural modifications can impact a drug’s susceptibility to these processes. B.) pH Sensitivity The pH of a drug’s environment can significantly affect its stability. Some drugs are sensitive to changes in pH, which can influence their solubility, chemical reactivity, and degradation rates.
- 45. C.) Interaction with Excipients Theexcipients used in drug formulations can interact with the active pharmaceutical ingredient (API) and impact its stability. Incompatibilities between the API and excipients can lead to degradation or changes in physical properties. D.) Microbial Contamination •Water-based formulations are prone to microbial growth, leading to spoilage. •Preservatives like benzalkonium chloride are added to prevent contamination. •Example: Eye drops require antimicrobial preservatives to maintain sterility.
- 46. External factors 1. Temperature Temperatureis a critical factor affecting drug stability. High temperatures can accelerate degradation pathways, while low temperatures can impact solubility and physical characteristics of drugs. 2. Humidity Humidity levels can impact the stability of drugs, particularly those sensitive to moisture. Moisture can trigger hydrolysis reactions and promote microbial growth in formulations.
- 47. 3. Light Light, especiallyUV and visible light, can induce photodegradation of drugs. Photo-sensitive compounds can undergo structural changes when exposed to light, leading to loss of potency and the formation of degradation products. 4. Oxygen Oxygen exposure can lead to oxidative degradation, where drugs lose electrons and undergo chemical changes. Packaging materials and storage conditions play a crucial role in minimizing oxygen exposure.
- 48. A well-designed stability studyprotocol should include the following information: 1. Number of batches 2. Containers and Closures 3. Orientation of storage of containers 4. Sampling time points 5. Test storage conditions 6. Test parameters.
- 49. Key Elements toDesign Stability Studies: The objectives of the study shall be defined within guidelines concerning with respect to regulations provided by FDA, EMA, or ICH. Knowledge and adherence to these guidelines are essential in defining conditions regarding how long a study should be conducted, any testing parameters, and what the acceptance criteria are to be to be compliant with regulations The stressors that may impact the stability of the drug are temperature differences, humidity, exposure to light, and conditions related to transportation. The appropriate test conditions can be identified using ICH guidelines, which classify different climatic zones. 1. Regulatory Compliance: 2. Selection of Test Conditions:
- 50. Regulatory Guidelines forStability Testing in India CDSCO is India’s regulatory authority under the Ministry of Health and Family Welfare. It follows Schedule M of the Drugs and Cosmetics Act, 1940, which outlines Good Manufacturing Practices (GMP) for pharmaceutical products. Stability testing is mandatory for New Drug Applications (NDA) and Abbreviated New Drug Applications (ANDA) before approval. (a) Central Drugs Standard Control Organization (CDSCO)
- 51. c. ICH StabilityGuidelines Followed in India India, as part of the ICH Global Cooperation Group (ICH-GCG), follows these guidelines: •ICH Q1A (R2): Stability Testing of New Drug Substances and Products. •ICH Q1B: Photostability Testing. •ICH Q1E: Evaluation of Stability Data (b) Indian Pharmacopoeia (IP) Guidelines The Indian Pharmacopoeia Commission (IPC) provides stability testing protocols for drugs marketed in India. IP standards align with ICH Q1A (R2) guidelines for new drugs and WHO recommendations for generic medicines.
- 52.