UNIT-I Preformulation. INDUSTRAIL PHARMACY -1pptx

B.pharm 5th sem

1. UNIT-I Introduction to Preformulation Studies By Mr. Madhav Korde

2. Preformulation Studies Introduction to Preformulation , goals and objectives, Study of physicochemical characteristics of drug substances. Physical properties : Physical form (crystal & amorphous), particle size, shape, flow properties, Solubility profile ( pKa , pH, partition coefficient), polymorphism Chemical Properties: Hydrolysis, oxidation, reduction, racemisation, polymerization BCS classification of drugs & its significant.

3. Preformulation Preformulation is an investigation of the physical and chemical Properties of a drug substance alone and when combined with excipients , to check its potential to be developed as an efficacious dosage form.

4. Preformulation Studies Goals and Objectives: 1) To establish the physicochemical parameters, 2) To establish the physical characteristics , 3) To establish the kinetic rate profile , 4) To establish the compatibility of the new drug substance with the common excipients, 5) To choose the correct form of a drug substance. The objectives of pre-formulation: 1) To develop elegant, stable, effective, and safe dosage forms . 2) Have to understanding of the physical description of a drug substance 3) Pre-formulation is the first step in rational development of a dosage form of a drug substance before the development of dosage form.

5. Importance of Preformulation in Drug Development Characterize Understand the drug's chemical and physical properties. Optimize Improve the drug's formulation and stability. Inform Guide the selection of appropriate manufacturing processes. Reduce Costs Minimize delays and failures in later development stages.

6. Physicochemical Properties Evaluation Chemical Properties Hydrolysis Oxidation Reduction Racemisation, Polymerization. Physical Properties Physical form, Polymorphism, Particle size, Particle shape, and Flow properties. . Solubility analysis Stability analysis

7. Formulation Screening and Optimization 1 Preformulation Identify critical quality attributes. 2 Initial Screening Evaluate excipient compatibility and stability. 3 Optimization Refine formulation to meet target product profile.

8. Regulatory Considerations in Preformulation ICH Guidelines Q6A, Q8, Q9, Q10, Q11 FDA Guidance SUPAC, CQA, QbD, PAT Data Package Support IND, NDA, ANDA submissions Quality by Design Incorporate QbD principles into preformulation

9. Formulation Design and Development Preformulation Characterize drug substance properties. Excipient Selection Identify suitable drug delivery systems. Formulation Development Optimize the drug product composition. Stability Testing Evaluate long-term stability and shelf life.

10. Challenges and Strategies in Preformulation Challenges Strategies Poor Solubility Salt formation, complexation, solid dispersions Polymorphism Screening, crystallization, amorphous form Physicochemical Instability Antioxidants, pH adjustment, physical stabilization Excipient Incompatibility Compatibility testing, excipient selection, formulation design

11. Physical Properties of Pharmaceuticals Understanding the physical properties of pharmaceutical compounds is crucial for successful drug development and formulation. From the molecular structure to the final dosage form, these properties play a critical role in determining the drug's stability, bioavailability, and overall efficacy. This presentation will provide an in-depth exploration of the key physical properties that shape the development of modern pharmaceuticals.

12. Physical Form: Crystal & Amorphous Crystalline Crystalline solids have a highly organized, repeating molecular structure. This gives them distinct physical properties, such as well-defined melting points, solubility, and stability. Crystalline forms are generally preferred for their predictable behavior and ease of characterization. Amorphous Amorphous solids lack the long-range molecular order found in crystals. They have higher internal energy and are typically more soluble than their crystalline counterparts. Amorphous forms can be challenging to stabilize, but they offer advantages in bioavailability and dissolution rate.

13. Particle Shape Spherical Spherical particles generally exhibit good flow properties and are easy to handle, making them a preferred shape for many drug formulations. Irregular Irregularly shaped particles can create challenges in processing, such as poor flow and packing, potentially leading to content uniformity issues. However, they may offer advantages in specific applications. Needle-like Needle-shaped particles can significantly impact powder flow, compaction, and dissolution behavior, requiring careful control and optimization during manufacturing.

14. Polymorphism Polymorphism refers to the ability of a drug substance to exist in multiple crystalline forms , each with distinct physical and chemical properties. This can significantly impact the drug's stability, solubility, and bioavailability. Identifying and characterizing polymorphic forms is a critical aspect of pharmaceutical development, often requiring a combination of analytical techniques like X-ray diffraction, thermal analysis, and spectroscopy . The selection and control of the optimal polymorphic form is essential for ensuring consistent product quality, reliability, and performance throughout the drug's lifecycle. Regulatory agencies closely scrutinize polymorphic changes, as they can significantly impact the safety, efficacy, and manufacturing of a drug product, requiring extensive characterization and justification.

15. Particle Size 1 Micronization Reducing the particle size of a drug substance to the micron range can significantly improve its dissolution rate and absorption, leading to enhanced bioavailability. 2 Nanonization Pushing particle size reduction even further, nanoparticles can offer improved solubility, permeability, and targeting capabilities for drugs with poor aqueous solubility. 3 Particle Size Distribution The overall distribution of particle sizes in a drug formulation can impact flow properties, content uniformity, and dissolution behavior, requiring careful control and characterization.

16. Characterization Techniques Microscopy Optical and electron microscopy techniques provide valuable insights into the morphology, size, and shape of pharmaceutical particles and crystals. Spectroscopy Analytical techniques like infrared, Raman, and nuclear magnetic resonance spectroscopy are used to identify and characterize the molecular structure and polymorphic forms of drug substances. Thermal Analysis Methods like differential scanning calorimetry and thermogravimetric analysis provide insights into the thermal behavior and stability of pharmaceutical materials. X-ray Diffraction X-ray diffraction is a powerful technique for identifying and quantifying the crystalline structure and polymorphic forms of drug substances and formulations.

17. Flow Properties Powder flow also known as Flowability, is defined as the relative moment of bulk particles among neighboring particles or along the container wall surface. Flowability- The capacity of any substance to flow is called flowability. Free-flowing or non-free-flowing / cohesive Changes in particle size, density, shape, electrostatic charge, and adsorbed moisture (arising from processing or formulation) significantly affect the powder’s flow properties Bulk density: When a high-dose capsule’s size or a low-dose formulation’s homogeneity is considered, bulk density plays a significant role. Drug Testing Process: Bulk drug sieved through a 40-mesh sieve poured into a graduated cylinder, Volume, and weight measured (gm/ml). Bulk Density= Mass(g)/Volume(ml) Tapped density: The graduated cylinder is tapped 1000 times on a mechanical tapper apparatus. The volume reaches a minimum – called tapped volume. Tapped Density= Mass(g)/Tapped Volume(ml) Methods of correction By milling, slugging or formulation Significance of Bulk Density Formulation Design: Determines the size and shape of tablets and capsules. Flow Properties: Predicts the flow characteristics of powder blends for uniform filling. Tablet Compression: Affects compaction properties and tablet hardness. Granulation: Helps select granulation methods and optimize process parameters. Blending: Ensures homogenous mixing of formulation components. Packaging Efficiency: Assists in selecting appropriate container sizes and ensures correct filling. Stability: Indicates moisture absorption tendencies, impacting product stability. Material Utilization : Optimizes raw material use, reducing waste and costs.

18. Flow Properties Powder flow properties: Powder flow properties depend on ( i ) particle size (ii) density (iii) shape (iv) electrostatic charge and adsorbed moisture that may arise from processing or formulation. A free-flowing powder may become cohesive during development . Carr's Index Also known as the Compressibility Index is a measure of the compressibility of a powder. It indicates the flowability and is calculated based on the powder's bulk density and tapped density. Carr’s Index= (TD-BD/TD) X 100 Hausner’s Ratio is another measure of a powder's flowability. It is calculated as the ratio of tapped density to bulk density. Hausner’s Ratio= TD/BD FLOW PROPERTIES ANGLE REPOSE HAUSNER RATIO Excellent 25-30 01- 1.11 Good 31-35 1.12- 1.18 Fair 36-40 1.19- 1.25 Passable 41-45 1.26- 1.34 Poor 46-55 1.35- 1.45 Very poor 56-65 1.46- 1.59 Very very poor >66 1.6

19. Flow Properties Angle of Repose Formula for measurement of flow property Where H = height of the pile R= radius of the base of the pile. ø= angle of repose.   Electrostatic Charge Pharmaceutical powders can easily accumulate static electricity , leading to particle agglomeration , poor flow, and content uniformity issues. Managing electrostatic charge is a critical aspect of powder handling and formulation development. Angle of repose ⬇ = Flow Property⬆

20. Solubility it is defined as the maximum amount of solute particles that can be dissolved in a given solvent at a constant temperature . It is important parameter to know before formulation. If solubility ⬆ , then absorption ⬆ . Ideally measured at 2 temperature, that is 4 o C and 37 o C . 4 o C – to ensure physical stability . 37 o C -to ensure Biopharmaceutical Evaluation . If solubility is less than 1g/ml, the absorption is very poor. Solubility Profile

21. The drug-solvent systems through which the drug is delivered help in the pre-formulation solubility studies. For example , Paracetamol's solubility in different solvents, including water, pH 1.2 buffer, pH 6.8 buffer, ethanol, and methanol, indicates moderate solubility in aqueous environments, and higher solubility in organic solvents suggesting it can be formulated in aqueous solutions for oral dosage forms. Formulation Implications: Oral Tablets/Syrups: Use water or suitable pH buffers . Injectables: Consider solubilizing in e thanol or other suitable co-solvents. Topical Formulations: Utilize ethanol or methanol for better solubility. Preformulation solubility studies involve pKa determination, temperature dependence, pH profile, solubility products, mechanisms of solubility, and dissolution rate. HPLC, UV spectroscopy, fluorescence spectroscopy, and gas chromatography are the analytical methods used for measuring solubility. The reverse phase HPLC technique provides accurate solubility data for most drugs by analyzing aqueous samples, achieving high sensitivity, and chromatographic separation from impurities or degradation products. Solubility Profile

22. 1 pKa ( Dissociation constant ) Th e conversion of ionized form to unionized form is known as ionization. The acid dissociation constant (pKa ) of a drug substance determines its ionization state and influences its solubility, stability, and absorption characteristics in the body . Unionized form ➡Lipid soluble ➡Lipophilic ➡ Absorption increased Ionized form ➡water soluble➡ hydrophilic ➡ Absorption Decreased Significance Tell the ionized and unionized form of the drug. When pH = pKa , that means 50% of the drug is ionized firm, and 50% of the drug is in unionized form. Methods of Determination of pKa of a Drug: UV or visible spectroscopy at a range of pH, Potentiometric titration, Solubilization, Dissolution Solubility Profile

23. 2 pH Power of Hydrogen OR Potential of Hydrogen The pH of the surrounding environment can dramatically impact the solubility of ionizable drugs, with potential implications for bioavailability and formulation development. Used to check whether the particles are acidic or basic. It also can affect the solubility of particles. By changing the pH the solubility of the acidic or basic drug can be changed. Solubility may be improved with the addition of acid or basic excipient. For example, the solubility of aspirin can be enhanced by the addition of an alkaline buffer. Dissolution is the process where a solute in a gaseous liquid, or solid phase dissolve in a solvent to form a solution. Solubility is the maximum concentration of solute that can be dissolved in a solvent at a given temperature. Dissolution can affect the onset of action , Intensity of action, Duration of respons e and Control overall bioavailability of the drug form. Means of increasing the solubility is the addition of co-solvent to the aqueous system. Eg. Ethanol, propylene glycol, and glycerine . 3 Dissolution. Solubility Profile

24. 4 Partition Coefficient (P) Partition coefficient is defined, as the ratio of un-ionized drug concentrations between the organic and aqueous phases , at equilibrium. The partition coefficient (log P) reflects a drug's lipophilicity and can provide insights into its ability to permeate biological membranes and reach the site of action. The formula for the partition coefficient is log P= Conc. Of Drug in Organic Phase/ Conc. Of Drug in Aqueous Phase. It has no unit. High log Po/w ➡ Hydrophobic drug. Low log Po/w ➡ Hydrophilic drug. Solubilization It is the process of incorporating the solubilizate (Compound that undergoes solubilization) into micelles. It may occur in the system consisting of a solvent association colloid and at least one other solubilizate . Approaches to increase solubility micronization , change in pH, and cosolvency . Solubility Profile 5

25. Stability analysis Stability of a drug is defined as the extent to which the product remains within the specified limit to identify strength , quality, and purity throughout the period of storage and use. Solid stability: Identify stable storage conditions for drugs in the solid state. Identify compatible excipients for formulation. Techniques used solid-state NMR powdered XRD raman spectroscopy dynamic. Dynamic vapor sovereignty . Differential scanning calorimetry(DSC) thermal gravimetric analysis furrier transform IR spectroscopy (FTIR). Drug-excipient stability profile includes melting point, colors/flavors, odor, taste, and particle size, which affect dissolution rate, suspendability , uniform distribution, penetrability, and lack of grittiness. Solution state stability: Solution state stability is a crucial part of the drug development process along the producing robust clinical supplies. Solution state stability involves the study of pH, cosolvent and ionic strength, temperature, and oxygen.

26. Factors Affecting Physical Properties Synthesis The synthetic route and conditions used to produce a drug substance can significantly influence its physical properties, such as crystal habit and polymorphic form. Formulation The choice and combination of excipients in a drug formulation can greatly impact the physical properties of the final product, including solubility, stability, and bioavailability. Manufacturing The various unit operations involved in drug manufacturing, such as milling, granulation, and tableting, can modify the physical properties of the drug substance and final dosage form. Storage & Stability Environmental factors like temperature, humidity, and light can induce changes in the physical properties of a drug product over time, potentially impacting its quality and performance.

27. Importance of Physical Properties 1 Drug Discovery Understanding the physical properties of drug candidates early in the discovery process can help guide the selection and optimization of promising molecules. 2 Formulation Development Thorough characterization and control of a drug's physical properties is essential for developing safe, effective, and stable pharmaceutical formulations. 3 Manufacturing & Quality Monitoring and maintaining the physical properties of drug substances and products is crucial for ensuring consistent quality, performance, and compliance throughout the product lifecycle.

28. Physicochemical Properties Evaluation Chemical Properties Hydrolysis Oxidation Reduction Racemisation, Polymerization . Physical Properties Physical form, Polymorphism, Particle size, Particle shape, and Flow properties. . Solubility analysis Stability analysis

29. Hydrolysis Hydrolysis is a chemical reaction where a drug molecule is broken down by adding water . Hydrolysis is a crucial consideration in Preformulation studies to ensure drug stability and efficacy . General Reaction: AB+H2O→AH+BOH Where AB is the drug molecule, H₂O is water, AH and BOH are the hydrolysis products . Importance in Drug Development : Stability : Hydrolysis can affect drug efficacy and shelf life. Formulation : Understanding hydrolysis aids in selecting appropriate excipients and packaging. Administration : Influences choice of dosage form and storage conditions. Factors affecting Hydrolysis: pH : Acidic or basic conditions can accelerate hydrolysis. Higher temperatures increase the hydrolysis rate. Catalysts can catalyze hydrolysis reactions. Chemical Properties

30. Hydrolysis Ex . Ester Hydrolysis Acid + Alcohol reaction involves carbon atom and oxygen rupture. Catalysts like mineral acids, alkalies , or certain enzymes supply H++ and OH− ions. Aspirin stability is highest at pH 2.4, pH 5 to 7, and pH 10; stability decreases with pH increase . Amide Hydrolysis: Hydrolytic reaction results Amide Acid + Amine. E.g.: Chloramphenicol, Nicinamides . Ring alterations: hydrolysis proceeds as a result of ring cleavage. Ring cleavage. E.g. Pilocarpine. Chemical Properties

31. Oxidation The environmental phenomenon of oxidation requires oxygen (or an oxidising agent), light, and trace metals that can catalyse the reaction . If molecular oxygen is involved, the reaction is rapid and termed auto-oxidation . Ex. 1. Rancidity of oil 2. R-OH R-COOH Alcohol Carboxylic acid Oxidation- Addition of Oxygen removal of Hydrogen loss of electron Antioxidant for Prevention Oil-soluble- free radical acceptor and inhibit free radical chain process. Examples , hydroquinone, BHA, BHT, lecithin, and tocopherol. Water soluble- oxidizes itself and prevents oxidation of drug. Examples- sodium meta-bisulfate, sodium bisulfate, acetylcysteine, ascorbic acid, sodium thiosulfate, sulfur dioxide, thioglycolic acid, thioglycerol , Preventing light exposure, Maintaining oxygen free environment, Storing the product at a low temperature   Chemical Properties O 2 Oxidation is crucial in preformulation studies for drug stability and efficacy, and proper understanding, testing, and preventive measures can enhance the shelf life of pharmaceutical products.

32. Reduction A chemical reaction in which a substance gains electrons, often involving the removal of oxygen or the addition of hydrogen . In pharmaceuticals, reduction can affect the stability and efficacy of drug substances . Reduction is influenced by various factors including the presence of reducing agents, pH, electrochemical environment, and temperature , which can all contribute to the reaction. Importance of Reductive Degradation in Drug Development Alters therapeutic effectiveness and safety profile. Aids in the formulation of stabilizing agents and packaging. Influences choice of excipients and delivery system design. Preventive Measures for Drug Reduction Use stabilizing agents like antioxidants. Minimize exposure to reducing environments in packaging. Store drugs in environments less likely to promote reduction. Example- Vitamin K Fat-soluble vitamin essential for blood clotting. Vitamin K (quinone form) can be reduced to hydroquinone. The reduced form can be less active or lead to different therapeutic effects. Stabilization: Using stabilizing agents and proper packaging to protect against reduction. Chemical Properties

33. Racemisation The racemization is the process in which one enantiomer of a compound, such as an L-amino acid, converts to the other enantiomer. Ex . L-Amino Acid ⇌ D-Amino Acid Where an L-enantiomer (left-handed) converts to a D-enantiomer (right-handed) or vice versa. Racemisation impacts chiral drug development stability, formulation, and administration strategies, potentially reducing efficacy or increasing toxicity, and influencing bioavailability and therapeutic outcomes. Racemisation is influenced by pH, temperature, solvent nature, and catalytic agents, with acidic conditions, higher temperatures, solvents, and certain metal ions accelerate the process. Preventive Measures for Drug Racemisation Maintain optimal pH for racemisation minimization. Store drugs at lower temperatures to slow racemisation . Use chiral stabilizers for enantiomeric purity. Use protective packaging materials against racemisation conditions Ex . Ibuprofen Racemisation Reaction : The S-enantiomer is active, while the R-enantiomer can convert to the S-enantiomer in vivo. Understanding racemisation helps in ensuring effective dosing. Chemical Properties

34. Polymerization In which small molecules(monomers), join together to form a large chain-like or network molecule, known as a polymer. 𝑛A → (A)𝑛​ Where A is the monomer, and (A) 𝑛 is the polymer formed . Polymerization Types Addition Polymerization: Monomers combine without losing small molecules. Example: Polyethylene formation from ethylene. Condensation Polymerization : Monomers join with small molecule elimination. Example: Polyester formation from diacids and diols. Chemical Properties

35. BCS Classification of Drugs The Biopharmaceutics Classification System (BCS) is a framework that categorizes drug substances based on their solubility and permeability . This classification system helps guide drug development and optimize bioavailability. The Biopharmaceutics Classification System (BCS) is a crucial guideline for predicting In-Vitro In-Vivo Correlations (IVIVC) conditions and for developing in-vitro dissolution specifications .

36. The BCS divides drug substances into four classes based on their solubility and permeability characteristics BCS Classification of Drugs CLASS SOLUBILITY PERMEABILITY ABSORPTION EXAMPLE I High High Well absorbed Diltiazem Propranolol Metoprolol II Low High Variable Nifedipine Carbamazepin Naproxen III High Low Variable Insulin Metformin Cimetidine IV Low Low Poor absorption Taxol Chlorothiazide Furosemide

37. Significance of BCS in Drug Development Class I drugs : Are best suited for controlled release formulation because they have high solubility and high absorption rate. 2. Class II drugs : Are required for some dosage modifications through drug size reduction ( Micronization ), use of surfacünts , development of microemulsion technique, etc. 3. Class III drugs: dosage form can develop through high-frequency capsules by manipulating gastric retention time, permeability enhancer etc , because they have low permeability. 4. Class IV drugs: are modified through all above mentioned techniques due to their less soluble and less permeable. Drugs in this class have poor bioavailability , influenced by factors like dissolution rate and gastric emptying, making them unsuitable for oral delivery, necessitating special technologies like nanosuspensions. BCS Classification of Drugs

38. Significance of BCS in Drug Development BCS classification helps determine the most appropriate formulation approaches to enhance solubility and permeability. BCS provides insights into the potential for drug absorption and bioavailability , which is crucial for drug development. BCS classification is used by regulatory agencies to make informed decisions on drug product approvals . BCS allows for the use of comparative in vitro testing to determine the bioequivalence of oral Immediate Release (IR) products. Assumes highly permeable and soluble drugs in rapidly dissolving drug products will be bioequivalent. Dissolution data can be used as a replacement for pharmacokinetic data to demonstrate bioequivalence of two drug products. Reduces cost of approving scale-up and post-approval changes without compromising public safety interests. Determines the influence of dissolution, solubility, and intestinal permeability on oral drug absorption from IR solid oral dosage forms. BCS Classification of Drugs

39. IVIV Correlation Expectation for Immediate Release Product Based on Biopharmaceutic Class BCS Classification of Drugs Class Solubility Permeability IVIV Correlation for IR Products I High High IVIV correlation if dissolution rate is slower than gastric emptying rate, otherwise limited or no correlation. II Low High IVIV correlation if in vitro and in vivo dissolution rate is similar, unless dose is very high III High Low Absorption (permeability) is rate determining and limited or no IVIV correlation with dissolution rate IV Low Low Limited or no IVIV comelation expected.

40. Factors Influencing BCS Classification Solubility Factors like pH, ionization state, and formulation excipients can impact a drug's solubility. Permeability Membrane transport mechanisms, physicochemical properties, and efflux transporters can affect drug permeability. Polymorphism Different polymorphic forms of a drug can exhibit different solubility and permeability characteristics. Particle Size Reducing particle size can improve solubility and dissolution, impacting BCS classification.

41. Implications of BCS on Bioavailability and Absorption 1 Class I Highly soluble and permeable drugs are readily absorbed, resulting in high bioavailability. 2 Class II Solubility-limited absorption can be improved through formulation strategies like micronization or amorphization. 3 Class III Permeability-limited absorption may be enhanced through the use of absorption enhancers or prodrug approaches.

42. Challenges and Limitations of BCS Classification Assessing Solubility Determining the appropriate solubility test conditions can be complex and subjective. Measuring Permeability In vitro permeability models may not always accurately predict in vivo absorption. Dynamic Nature BCS classification can change due to factors like formulation changes or patient factors.

43. Applications of BCS in Formulation Design Solubility Enhancement BCS guides the selection of appropriate solubility-enhancing techniques, such as use of surfactants or cyclodextrins. Dissolution Optimization BCS informs the design of dissolution testing and the development of controlled-release formulations. Permeability Improvement BCS enables the selection of permeability-enhancing strategies, including the use of absorption promoters.