This document discusses key concepts in preformulation for solid dosage forms like tablets. It defines preformulation as investigating the physical and chemical properties of active ingredients alone and in combination with excipients to obtain information for developing stable, high quality dosage forms. Important properties to study in preformulation include solubility, acid/base dissociation, polymorphism, surface characteristics, flowability and compressibility which influence formulation development, manufacturing and stability. Understanding these properties helps ensure the dosage form will have the required efficacy, safety, acceptability and stability.
This document discusses key concepts in preformulation for solid dosage forms like tablets. It defines preformulation as investigating the physical and chemical properties of active ingredients alone and in combination with excipients to obtain information for developing stable, high quality dosage forms. Important properties to study in preformulation include solubility, acid/base dissociation, polymorphism, surface characteristics, flowability and compressibility which influence formulation development, manufacturing and stability. Understanding these properties helps ensure the dosage form will have the required efficacy, safety, acceptability and stability.
This document discusses key concepts in preformulation for solid dosage forms like tablets. It defines preformulation as investigating the physical and chemical properties of active ingredients alone and in combination with excipients to obtain information for developing stable, high quality dosage forms. Important properties to study in preformulation include solubility, acid/base dissociation, polymorphism, surface characteristics, flowability and compressibility which influence formulation development, manufacturing and stability. Understanding these properties helps ensure the dosage form will have the required efficacy, safety, acceptability and stability.
Universitas Sriwijaya Genap 2013/204 Solid dosage form (tablet) - Preformulation Pertemuan ke - 2 Concept of quality What is quality? Consumer returns not goods being returned Concept of Quality Quality does not just happen Quality has to be designed and built into a product during the entire manufacturing process This process has to be validated What is quality for dosage form? 1. Efficacy 2. Safety 3. Acceptability 4. Stability What is quality for dosage form based on? 1. Formula 2. Method 3. Process 4. Equipments/Tools 5. Packaging Preformulation It is essential that certain fundamental physical and chemical properties of the drug molecule and other deri ved properties of the drug powder are determined. This information dictates many of the subsequent events and approaches in formulation development. This first learning phase is known as preformulati on History of Preformulation What is preformulation? Preformulasi adalah pengamatan (investigasi) sifat fisika, kimia bahan aktif baik sendiri maupun dalamkombinasinya dengan eksipien dengan tujuan untuk memperoleh informasi lengkap tentang hal-hal penting dalampengembangan suatu bentuk sediaan yang stabil dan bermutu (berkualitas) Purpose of preformulation To establish and discover necessary physicochemical properties of new substances To determine its kinetic rate profile To establish its physical characteristic To establish its compatibility with excipients New compound preformulation Two fundamental properties are mandatory for a new compound: 1. Intrinsic solubility (C0) 2. Dissociation constant (pKa) lipophilicity Why? Correlates with BCS (Biopharmaceutical Classification System) 60% of drugs are either Class 2 (low solubility) or Class 4 (low solubility and low permeability) Properties Observed in Preformulation 1. Organoleptic 2. Partition coefficient 3. Acid/base dissociation constant and permeability through biological membrane (pKa, pKb) 4. Solubility (intrinsic, apparent) and dissolution 5. Purity 6. Polymorphism and crystal form 7. Surface characteristic (surface area, porosity, pore volume) 8. Flowability 9. Compactibility/compressibility 10. Wettability 11. Other (hygroscopicity, density, melting point, vapour pressure) Organoleptic Using senses Qualitative result Useful masking bitter taste (ex: chloramphenicol) Beberapa terminologi yang digunakan untuk mendeskripsikan serbuk Warna Bau Rasa Putih buram Tajam Asam Krimkekuningan Sulfurous Pahit Coklat Aroma buah Lembut Mengkilap Aromatik Kuat Tidak berbau Manis Tidak berasa Partition coefficient What is it? The ratio of the concentrations of a solute in two immiscible or slightly miscible liquids PC = C (np)/C (p) Why? Biological membrane lipophilic Correlates with solubility pKa/pKb and membran permeability What? quantitative measure of the strength of an acid in solution Majority of drugs are in weak acid/base form In the presence of liquid, there will be ionized and unionized form Henderson-Hasselbach pH = pKa + log (i)/log(ui) Drugs should be targeted for absorption at its compatible/correct biological location (+/- 1-2 of its pKa/pKb) pKa/pKb and membran permeability Unionized less polar pass through biological membrane easier %ionization = I / I+UI x 100% Drugs absorption transport system: passive diffusion, active transport, facilitated transport Partition pH hypothesis = most drugs are absorbed from GI through passive diffusion, which amount relative towards the fraction of unionized drugs Solubility and dissolution Solubility = static Dissolution = rate process Solubility is the analytical composition of a saturated solution expressed as a proportion of a designated solute in a designated solvent. Dissolution is the process by which a solute forms a solution in a solvent. Dissolution is a kinetic process and it is quantified by its rate Solubility and dissolution Rate of dissolution can affect onset, duration, response intensity as well as bioavailability of drugs. Noyes whitney equation (rate of dissolution) dM/dt = DS(Cs-C)/h Solubility and dissolution Purity Correlates with efficacy and safety of a drug. Products used in a drug MUST be pharmaceutical grade Quality specification are specified in pharmacopeia Polymorphism Raw material drugs are usually in crystalline and amorph form Useful information to gain knowledge about efficacy and stability Ex: novobiosin and chloramphenicol palmitate has better efficacy in amorf form Crystalline form usually has lower internal energy, thermodinamically more stable than amorph, so often less soluble than amorph form Surface characteristic Has effect on mixing and formulation of tablets (especially on fluidity) Drugs with spheric shape flow better (v,s = 6). The bigger v,s the more amorf the particle. With the same diameter but bigger v,s the fluidity of particle is less. Drugs smaller particle size has better dissolution but lessen the fluidity and stability Classification: - COARSE POWDER : 1000 m - CONVENTIONAL POWDERS : 50 1000 m - FINE PARTICLES : 1 50 m - SUB MICRON PARTICLES : 0,1 1 m - MICRONIZED : < 0,1 m Flowability/fluidity Has effect on tablet formulation, mixing and weight uniformity. Factors that influence fluidity of powder: - Particle size - Shape of particles - Density of particle - Porosity of pwder - Electrostatic forces - Humidity Compressibility and compactibility Compactibility: is the ability of the powdered material to be compressed into a tablet of specific tensile strength Compressibility: its ability to decrease in volume under pressure Compact: static Compress: dinamic Correlates with particle deformation in tablet compression Wettability Has effect on granulation, water penetration (disintegration) and adhesion of material (in coating) Wettability = sudut kontak yang terbentuk antara cairan dan padatan Hydrophobic contact angle = 90 degrees Can be improved with surfactant and hydrophilization Stability 5 categories of stability that needs to be taken into account: 1. Chemical 2. Physics 3. Microbiologic 4. Therapeutic 5. Toxicologic Others Density compactibility, compressibility Vapour pressure lost of active ingredients, interaction with excipents, adsorption/sorption into packaging Melting point manufacture consideration (drying/heating), also for purity Hygroscopicity manufacture consideration (humidity), interaction with excipients, shelf life (stability)