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INDUSTRIAL PHARMACY-I (BP 502 T.) UNIT 1 (IP-1)

This unit focuses on the evaluation of the physical and chemical properties of drug substances before formulation. It includes particle size, crystal form, solubility, pKa, partition coefficient, stability, compatibility studies, and the Biopharmaceutical Classification System (BCS) to support the development of safe, effective, and stable pharmaceutical dosage forms.

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Third Year B. Pharma Industrial Pharmacy - I (BP 502 T) Presented by, Mr. Chetan S. Mali
UNIT 1 PREFORMULATION STUDIES Presented by, Mr. Chetan S. Mali
PRE-FORMULATION STUDIES • Before developing a formulation like tablets, capsules, liquid orals we study the suitability of new drug or drug and excipients for the chosen formulation which is called Preformulation. • Preformulation studies are the first step in drug development. • They are done before preparing the dosage form. • Preformulation studies help identify potential issues with the drug substance that may affect its performance, stability or manufacturability. • Preformulation studies are a critical stage in the development of pharmaceutical products. • To study the physical and chemical properties of the drug. • To help develop a safe, effective, and stable medicine.
 Goal and Objectives • Study the physical and chemical properties of the drug. • Select compatible excipients (ingredients) for the formulation. • Develop a safe, effective, and stable dosage form with good bioavailability. • Develop new dosage forms of existing drugs. • Evaluate the drug's stability to determine shelf life and storage conditions. • Ensure the formulation can be manufactured on a large scale without losing its quality, stability, or effectiveness. • To help adjustment of pharmacokinetic properties.
 Study of physiochemical properties of drugs • Physicochemical properties are the physical and chemical characteristics of a drug. • These properties affect the drug's formulation, stability, bioavailability, and therapeutic effectiveness. A) Physical properties 1. Organoleptic properties 2. Physical Form 3. Particle Size 4. Particle Shape 5. Flow Properties 6. Solubility Profile 7. Polymorphism B) Chemical Properties 1. Hydrolysis 2. Oxidation 3. Reduction 4. Racemisation 5. Polymerization
A) Physical Properties • Physical properties are the characteristics of a drug that affect its formulation and manufacturing. • Select the appropriate dosage form. • Improve the manufacturing process. • Ensure product stability. 1) Organoleptic properties • Those properties which can find out through our sensory organ E.g. • Colour • Order • Taste • Texture
2) Physical Form: • The physical form of a drug is the state or structure in which it exists, such as crystalline, amorphous. • It affects the drug's solubility, dissolution rate, stability, and bioavailability, which influence formulation.  Solid dosage forms are of two types: I. Crystalline solids II. Amorphous solids 1. Crystalline solids • The dosage form that features highly ordered arrangements of their particles (atoms, ions & molecules) in microscopic structure are called crystalline dosage form. 2. Amorphous solids • The solids in which the particles are not arranged in any specific order are known as Amorphous Solids.
Crystalline Solids Amorphous Solids • Molecules are arranged in a regular and orderly pattern. • Molecules are arranged in an irregular and random pattern • Have a definite shape. • Do not have a definite shape. • Have a sharp melting point. • Do not have a sharp melting point (melt over a range). • More stable. • Less stable. • Less soluble in water. • More soluble in water. • Slower dissolution rate. • Faster dissolution rate. • Lower bioavailability. • Higher bioavailability. • Example: Sodium chloride, Sugar. • Example: talc powder • They are practically incompressible • They are practically compressible • They have high rigidity (Hard) • They have less rigidity
3) Particle Size • Particle size is an important parameter in Preformulation studies because it affects the drug's physicochemical and biopharmaceutical properties. • It influences the drug's solubility, dissolution rate, bioavailability, and manufacturing process. • Controlling particle size helps ensure consistent drug performance and easy manufacturing.  Determination of Particle Size The following methods are used to measure particle size and particle size distribution: • Microscopy Optical Microscopy Electron Microscopy • Sieving • Sedimentation Techniques • Coulter Counter
4) Particle Shape • Particle shape is the geometric form of drug particles. • In Preformulation studies, particle shape affects the physical and chemical properties of the drug. Common shapes • Spherical • Cubical • Irregular • Spherical particles have better flowability. • Irregular particles have a larger surface area, which increases the dissolution rate. • Irregular particles pack less efficiently, causing variation in bulk density and tapped density. • Particle shape affects tablet compression. • Irregular particles may deform or fracture under pressure.
5) Flow properties • Flow properties show how powders and granules flow during manufacturing processes such as mixing, granulation, compression, and filling. • Poor flow can cause non-uniform drug products, especially in tablets and capsules. Blending: • Ensures uniform mixing of drug and excipient particles. Filling • Helps in accurate filling of tablets and capsules. Compression • Poor flow can cause variation in tablet weight, hardness, and drug content, affecting the final product quality.
 Factors • Larger particles tend to have better flow due to reduced cohesive forces. • Spherical particles generally flow more easily due to less friction. • Particles with high moisture content tend to clump or adhere to each other  Measurement of Flow Properties a. Bulk Density (BD) • Bulk density is the mass per unit bulk volume, including the space between particles. Formula: BD Mass Bulk Volume b. Tapped Density (TD) • Tapped density is the density of a material after tapping, which allows the particles to settle closely together. Formula: TD Mass Volume after tapping
• The flowability of powder can be determined by calculating Carr's Index and Hausner Ratio. c. Carr's Index (CI) • < 15% = Good Flow • > 25% = Poor Flow d. Hausner Ratio (HR) • < 1.25 = Good Flow • > 1.4 = Poor Flow
e. Angle of Repose: • The angle formed between the horizontal surface and the slope of a pile of powder is called the Angle of Repose. Formula h tan θ = r θ = Angle of Repose h = Height of the powder pile r = Radius of the powder pile Flow Properties: • Angle of Repose < 30° = Good Flow • Angle of Repose > 40° = Poor Flow
6) Solubility Profile • Solubility is the maximum amount of a drug that can dissolve in a fixed volume of solvent. • It is an important parameter in Preformulation studies because it affects the drug's bioavailability, absorption, and therapeutic effect. • Good solubility helps the drug to be absorbed by the body in its active form.  Importance of Solubility in Preformulation • Bioavailability: For oral drugs, the drug must dissolve in GIT fluids before it can be absorbed. • Poor solubility leads to low bioavailability. • Drugs with low solubility may require higher doses, increasing the risk of side effects. • Poor solubility makes granulation and compression difficult, affecting product quality. • Solubility helps in selecting the appropriate dosage form.
a. PH (Power of hydrogen) • Used to check that particle acidic or basic • It is an important factor in Preformulation because it affects the solubility, stability, and absorption of a drug. • E.g. Solubility of aspirin can be enhanced by addition of alkaline buffer b. Ionization Constant • The conversion of ionized form to unionized • Ionized drugs are more soluble in water. • Unionized drugs cross biological membranes more easily, so they are absorbed better. c. Partition Coefficient • The partition coefficient shows how a drug is distributed or dissolved between two immiscible (non-mixing) solvents. (Lipophilic or Hydrophilic)
7) Polymorphism • The word Polymorphism comes from the Greek words Poly = Many and Morph = Forms. • When a substance exists in more than one crystalline form with the same chemical composition but different physical properties it is called polymorphism. Example: Carbon, Phosphorus, Sulphur.  Importance of Polymorphism in Preformulation • Different polymorphs have different solubility. • Higher solubility gives better drug absorption and therapeutic effect. • Different polymorphs have different physical and chemical stability.
B) Chemical Properties • Chemical properties are studied to identify the factors that cause drug instability (degradation of drug substance) through chemical reactions during Preformulation. Chemical properties evaluated: 1. Hydrolysis 2. Oxidation 3. Reduction 4. Racemisation 5. Polymerization 1) Hydrolysis • Hydrolysis is one of the most common drug degradation reactions. It is the breakdown of a drug due to its reaction with water (moisture). • The decomposition of drug molecule due to reaction with water and get hydrolyse. • It is important because it affects the drug's shelf life, efficacy, and safety, especially in solutions, suspensions, and injections.
Prevention • Use moisture resistance pack for drug substance • Make distance from moisture • Control PH (Use buffer) • By modification in chemical structure 2) Oxidation • Oxidation is another common degradation pathway studied in Preformulation studies. • It involves the loss of electrons by a molecule, often due to a reaction with oxygen, resulting in chemical instability. • Addition of oxygen, Removal of Hydrogen • Oxidation can affect the potency, safety, and efficacy of a drug. E.g. Rancidity of oil
Prevention of Oxidation • Use of antioxidants (Ascorbic acid, Sodium Metabisulfite) • Protect from light • Store in an inert atmosphere • Refrigeration 3) Reduction • Reduction is a less common but important degradation pathway studied in Preformulation studies. • It involves the gain of electrons, leading to a decrease in the oxidation state of the drug. • Addition of hydrogen, Removal of oxygen. Prevention of Reduction • Avoid reducing agents (Sodium Metabisulfite) • Use protective packaging • Use chelating agents
4) Racemization • It is the process in which one enantiomer of compound is converted into another • Which can alter pharmacokinetic, pharmacological and taxological properties • The process is affected by pH, temperature, light. Example: • L-Epinephrine is 15–20 times more active than D-Epinephrine. Prevention • PH control • Temperature control • Proper solvent selection • Use of stabilizers
5) Polymerization • It is a chemical reaction where two or more drug molecule combine to form high molecular weight compound. • Polymerization is the formation of polymers by combining monomers (Degradation occur) • It is an important process in drug formulation because it affects the quality of the final product. • Loss of potency, and sometimes toxicity occur. Uses of Polymerization in Preformulation • Modifies drug release • Enhances drug stability • Increases drug solubility • Maintain storage condition
BCS (Biopharmaceutical Classification System) • BCS stands for Biopharmaceutical Classification System. • It is a system used to classify drugs based on their solubility and permeability. • It helps to predict drug absorption and bioavailability and is widely used in drug development and regulatory approval.  Types 1. Class I 2. Class II 3. Class III 4. Class IV
1. Class I • Drugs are highly soluble. • They easily cross the intestinal membrane. • They are rapidly absorbed after oral administration. • They have good bioavailability. • These drugs are ideal for oral dosage forms. Examples: Metoprolol, Propranolol. 2. Class II • Drugs have poor solubility. • They easily cross the intestinal membrane. • Bioavailability can be improved by increasing solubility. • Suitable for controlled-release formulations. Examples: Ketoconazole, Ibuprofen, Phenytoin.
3. Class III • Drugs have good solubility. • They cross the intestinal membrane poorly. • Bioavailability may be affected by changes in the gastrointestinal membrane. • Food can affect drug absorption. Examples: Cimetidine, Atenolol, Acyclovir. 4. Class IV: • Drugs have poor solubility and poor permeability. • They show poor absorption and low bioavailability. • They often require novel drug delivery systems. • Drug development is more challenging. Example: Furosemide.
Solubility Permeability E.g. • Class 1 High High Metoprolol • Class 2 Low High Ibuprofen • Class 3 High Low Acyclovir • Class 4 Low Low Furosemide  Significance • Useful in formulation of dosage form • Used to develop quality control • Decide bioavailability • Used to study IVIVC (In vitro in vivo correlation) • In vitro (Out side the body E.g. Solubility) • In vivo (Inside the body E.g. Bioavailability/ Absorption)
 Application of Preformulation Considerations in Dosage Forms • Preformulation studies help to select proper excipients. • Preformulation is an important step in drug development. It studies the physical, chemical, and mechanical properties of a drug to develop a stable, safe, and effective dosage form. • The main goal is to collect information needed for formulation development.  Solid Dosage Forms 1. Solubility • For solid dosage forms, drug solubility in aqueous and non-aqueous solvents is very important. • Poor solubility can lead to low bioavailability. Solubility can be improved by: • Salt formation • Use of surfactants • Particle size reduction
2. Particle Size: • The size and distribution of drug particles affect the dissolution rate and bioavailability of the drug. (Small particle size) • Micronization and other particle size reduction techniques are used to obtain the optimal particle size. • Important for uniform blending of powder. 3. Polymorphism: • A drug can exist in different crystalline forms (polymorphs). • These forms affect the drug's stability, dissolution, and bioavailability. • Selecting the most stable polymorph is important for solid dosage forms.
4. Hygroscopicity • Some drugs absorb moisture from the air, which can change their properties. • Preformulation studies help determine the need for moisture protection during formulation and storage. 5. Flow Properties • Good flow properties are important for tablet and capsule manufacturing. • Poor flow can cause weight variation and poor content uniformity. • Flow can be improved by using flow enhancers or granulation.
 Liquid Dosage Forms 1. Solubility • Solubility is very important for liquid formulations. • Drug should be soluble in chosen solvent Drugs with poor solubility can be improved by: • pH adjustment • Co-solvency • Use of surfactants 2. Viscosity Liquid formulations should have appropriate viscosity for: • Easy pouring • Accurate dosing • Viscosity enhancers such as gums or polymers are added to syrups and suspensions.
3. Stability • The drug should remain chemically stable in solution. Stability studies include: • Hydrolysis • Oxidation • Photodegradation • Antioxidants, preservatives, and proper packaging are used to improve stability. 4. PH • The pH of a liquid formulation is important for drug stability and solubility. • Buffers are added to maintain a stable pH throughout the shelf life of the product.
5. Suspension Stability • For suspensions, particle size, particle size distribution, and sedimentation rate are important to maintain uniformity. • Suspending agents are added to improve the stability of the suspension. 6. Taste Masking • Oral liquid formulations often require taste masking to improve palatability. • Sweeteners and flavouring agents are added to mask the unpleasant taste of the drug. 7. Preservatives • To avoid microbial growth in aqueous solvent E.g. parabens, benzoates
 Parenteral Dosage Forms 1. Sterility • Parenteral products must be sterile. Preformulation helps select the appropriate sterilization method. 2. Solubility • For parenteral formulations, high solubility is essential because the drug is administered directly into the bloodstream. 3. Isotonicity • Parenteral formulations should be isotonic with body fluids to prevent irritation and tissue damage. 4. PH • The pH should be physiologically acceptable and should maintain the stability of the drug.
5. Stability • Since parenteral are usually aqueous solutions, the drug should be stable against hydrolysis and oxidation. 6. Solvent Selection • For poorly water-soluble drugs, non-aqueous solvents such as propylene glycol, polyethylene glycol (PEG), or oils are used in parenteral formulations. 7. Particle Size • In parenteral suspensions, particle size affects the injectability and distribution of the drug in the body.