Preformulation Studies PDF

# UNIT I ## PREFORMULATION STUDIES ### CONTENTS - Introduction to Preformulation - Goals and objectives - Study of Physico - Chemical Characteristics of Drug Substances - BCS Classification of Drugs - Application of Preformulation Considerations and its Impact on Stability of Dosage Forms like -...

# UNIT I ## PREFORMULATION STUDIES ### CONTENTS - Introduction to Preformulation - Goals and objectives - Study of Physico - Chemical Characteristics of Drug Substances - BCS Classification of Drugs - Application of Preformulation Considerations and its Impact on Stability of Dosage Forms like - solid dosage forms, liquid dosage forms and parenterals ## INTRODUCTION - Prior to development of a formulation or dosage form, it is essential that certain properties of a drug molecule are to be determined. - This information decides many of the subsequent events and approaches in formulation development. - **Preformulation** - phase of research and development in which the physical and chemical properties of a drug molecule in order to develop safe, effective and stable dosage form. - **Preformulation** commences when a newly synthesised drug shows a sufficient pharmacological promise in animal model to warrant evaluation in man. - First step in rational development of a dosage form of a drug substance. ## GOALS & OBJECTIVES - Main objective is to generate information useful to the formulation in developing most stable and bioavailable dosage form that can be produced. - Establish necessary physicochemical parameters of new drug substance that can affect the drug performance and development of an efficacious stable and safe dosage form. - Determine kinetic rate profile. - Establish physical characteristics. - Establish compatibility with common excipients. - Provide insights into how drug products should be processed and stored to ensure their quality. - To develop an optimal drug delivery system. ## PHYSICO-CHEMICAL CHARACTERISATION ### A. Physical Properties of Drug Substances - Organoleptic Characterisation - Bulk Characterisation - Solubility Profile ### B. Chemical Properties of Drug Substances - Hydrolysis - Oxidation - Reduction - Racemisation - Polymerisation ## A. PHYSICAL PROPERTIES OF DRUG SUBSTANCES - The physical properties of drug molecules can affect the structure and stability formulations and may also alter the bioavailability of the drugs from the dosage forms. - Hence, physical properties of drugs are important in the dosage form design. - There are three categories of physical properties influence dosage form design. ### i) Organoleptic Characterisation - Refers to the evaluation of drug on the basis of colour, odour, texture and taste. - Product should be good in appearance. - Colour should be eye-appealing. - Odour and taste should be pleasant. - Absence of impurities and should be in the purest form. ### ii) Bulk Characterisation - Bulk characterisation of drug molecules involves the characterisation of various solid state properties that could change during the process development. - Variability of bulk characterisations, significantly prove subsequent events and approaches in drug development process. #### Bulk Characterisation includes :- - **Crystallinity, Amorphism,** and **Polymorphism** - physical properties - Fine particle characterisation - Density of Drug Substances - Powder Flow Properties. #### Crystallinity, Amorphism, and Polymorphism - Physical properties ##### 1. Crystallinity - Crystal compounds are characterised by repetitious spacing of constituent atoms or molecules.  - Crystals can be of different shapes. E.g cubic, tetragonal, orthorhombic etc. - The crystal habit and crystal internal structure of a drug can affect the bulk and flow properties as well as chemical stability. - Crystal habit - outer appearance of a crystal. - Internal structure - molecular arrangement within the solid. - Degree of crystallinity affects the hardness, density, transparency, and diffusion. - Crystallinity has a greater affect on the absorption of drugs. - Crystalline compounds may have stoichiometric or non-stoichiometric adduct, where the non-stoichiometric adduct is undesirable and removed. ##### 2. Amorphism - Amorphous compounds are those whose atoms or molecules are randomly placed.  - Internal structure shows a major distinction whether the solid is crystalline or amorphous. - Some drugs can exist in amorphous state. They are typically prepared by rapid precipitation, lyophilization. - Such drugs represent highest energy state, or higher thermodynamic energy than the crystalline state. - Amorphous form are less stable than its crystalline state. - The solubility of amorphous form is greater than its crystalline state. - Upon storage, amorphous solids tend to revert to more stable forms. Thermodynamic instability is a major disadvantage for developing a dosage form. ##### 3. Polymorphism - When a substance exists in more than one crystalline form - the different forms are designated as Polymorphs and the phenomenon - Polymorphism.  - Polymorphs are of two types - Enantiotropic polymorphs and Monotropic polymorphs - Enantiotropic polymorphs - is the one which can be reversibly changed into another form by altering the temperature or pressure. - Monotropic polymorphs - is the one which is unstable at all temperatures and pressures. - Polymorphs differ from each other respect to their physical properties like solubility, melting point, density etc. - Depending on the stability on e form will be more stable than the other. Such stable forms have - lower energy state, high melting point, least aqueous stability. - Other forms are called metastable forms with the opposite properties. - Determined by Differential Scanning Calorimetry, X-Ray Diffraction methods. ### Fine Particle Characterisation - Bulk flow, formulation homogeneity and surface controlled processes such as dissolution and chemical reactivity are directly affected by size, shape, an surface morphology of drug particles. ##### 1. Particle Size - Size affects - drug release from dosage forms, drug absorption, therapeutic action, physical stability of dosage forms like suspensions and emulsions, flow properties of powders like interference in the flowability of the powder. - Particle size generally denoted in micrometers. - Determined by four different methods :- - Optical microscopy - gives number distribution. - Sedimentation methods - using Andreasen Pipette method. - Conductivity methods - based on the principle of change of light intensity using methods like - counter coulter method, light scattering method. ##### 2. Particle Shape - Shape has a influence on the surface area, flow properties, packing and compaction of the particles. - Spherical particles have minimum surface area and better flow properties. - Shape also influences rate of dissolution of drugs. - Determination of particle size - microscopy method and light scattering method.  ##### 3. Particle Surface Area - Size and surface area are inversely related to each other. - Smaller the drug particle, greater the surface area. - Maximum surface area ensures better solubility. - Determination of particle surface area - adsorption method and air- permeability method.  ### Density of Drug Substance - Densities of particles should be observed carefully because sometimes particles can be hard and smooth in one case, and rough and spongy in another. - Density is defined as weight per unit volume. - Four different types of densities are generally observed :- ##### 1. True Density - Density of the material itself. - True density = Powder Weight / True Volume - True volume - volume obtained excluding the void volume and intra particle pores. - Measure using the gas displacement or liquid displacement method. ##### 2. Granule Density - Determined for granules that are employed in the manufacture of tablets. - Granule density = Granule Weight / Granule Volume - Granule density measured using mercury displacement method. ##### 3. Bulk Density - Defined as the mass of the powder divided by the bulk volume. - Bulk density = Bulk Weight / Bulk Volume - Bulk density value indicates the volume of all pores within the powder sample. ##### 4. Tapped Density - Ratio of the mass of the powders to the volume occupied by powder after it has been tapped for a defined period of time. ### Flow Properties of Materials - Flow property can be affected by a number of factors like - changes in particle size, shape, surface area, density, frictional forces, van der waals forces etc. - Efficient flow of particles is needed for an effective formulation. In case of liquid materials, flow properties are measured using rheology and thixotropy. ##### 1. Hausner's ratio - Number that is correlated to the flowability of powder or granular material. - Hausner's Ratio = Tapped Density / Bulk Density ##### 2. Carr's Compressibility Index - Ability of powder to decrease in volume under pressure. - Carr's Compressibility Index = {[Tapped - Bulk Density] / Tapped Density } * 100 | CARR'S INDEX | HAUSNER'S RATIO | FLOWABILITY | |--- |--- |--- | | 5-10 | 1.00-1.11 | Excellent | | 11-15 | 1.12-1.18 | Good | | 16-20 | 1.19-1.25 | Fair | | 21-25 | 1.26-1.34 | Passable | | 26-31 | 1.35-1.45 | Poor | | 23-37 | 1.46-1.59 | Very poor | | >38 | > 1.60 | Extremely poor | ##### 3. Angle of Repose - Indirect method of quantifying powder's flowability, because of their relationship with inter-particle cohesion. - Angle of repose = maximum angle between the surface of a pile of a powder, and a horizontal plane. Such an angle is calculated using, - tan θ = height of conical heap / radius of horizontal plane of powder | ANGLE OF REPOSE | FLOW PROPERTY | |---|---| | <25 | Excellent | | 25-30 | Good | | 30 - 40 | Passable | | >40 | Very Poor | ##### 4. Moisture Content - reduces the flow property of the particles. ##### 5. Nature of Particles - coarse and fine particules shows a goof low property. ##### 6. Particle Size - particle size when smaller, flow property is better. ### iii) Solubility Analysis of Drug Substances - Preformulation solubility studies focus on drug - solvent systems that could occur during the delivery of a drug candidate. - Understanding the drugs solubility profile and possible solubilisation mechanisms provide a basis for formulation work. #### Solubility Analysis includes :- - pKa determination - pH solubility profile - Partition Coefficient ### pKa determination - As the drug needs to be introduced via a route of administration, a dosage form should be selected. - Most of the drugs are absorbed even before the therapeutic effect takes place. - The cell membrane acts as a barrier for most of the drugs to be absorbed as it is a liphophilic barrier. Charged hydrophilic heads face outwards and non-charged hydrophobic part faces to the middle part. - Uncharged layer repels the charged drug substances. Non-ionic species diffuse readily through the cell membrane. - Taking an example of an acid "HA", it can dissociate into A^- the conjugate base of an acid and a hydrogen ion H⁺ . - K_a = [A^- ][H⁺ ] / [HA] where, K_a is the acid dissociation constant. - pKa is the negative logartihm of K_a. - pKa = - log K_a - K_a - function of the amount of drug that exist in the unionised form. - pKa - gives the strength of the acid or base used. - Percentage of drug ionised can be found by the Henderson Hasselbach equation. - For acidic drugs, pH = pKa + log [ionized form/unionized form] - For basic drugs, - When the concentration of ionized and unionized form becomes equal, pH = pKa, since log 1 = 0. - Lower the pKa, higher the acidic strength. - pKa value can be determined by analytical methods like, UV - Visible spectroscopy, potentiometric titrations etc. - GIT has an entire range pH of 1-8. stomach is said to have a pH range of 1-3 and the intestine is said to have a ph range of 5-8. ### pH solubility profile - pH is the negative logartihm of H⁺ ion. - Solubility of many compunds depend strongly on the pH of the solution. - Changing the pH, can make a difference in the solubility of the acidic or basic drugs. | Drugs | pKa | pH/ Site of Absorption | |---|---|---| | Very weak acid | > 8.0 | Unionised at all pH/ absorption throughout GIT | | Moderately weak acid | 2.5-7.5 | Unionised in gastric pH, ionised in intestinal pH/ absorption site - stomach | | Strong acid | <2.5 | Ionised at all pH / poor absorption | | Very weak base | <5.0 | Unionised at all pH/ absorption through the GIT | | Moderately weak base | 5.0-11.0 | Ionised in gastric pH, unionised in intestinal pH / absorption site - intestine | | Strong base | >11.0 | Ionised at all pH / poor absorption | ### Partition Coefficient - P.C is the ratio of the concentration of solute in two immiscible or slightly miscible liquids, when it is in equilibrium across the interface between them. - Generally refers to the concentration ratio of un-ionised species of a compound. - P_o/aq or K_o/aq =(conc. of drug in organic phase)/ (conc. of drug in aqeous phase) - Partition coefficient measures how hydrophilic or hydrophobic a drug substance is. - Estimates the distribution of drugs in the body. - Hydrophobic drugs distribute in the hydrophobic areas such as lipid bilayers of the cells. - Hydrophilic drugs are found in the hydrophilic areas such as blood serum. - Determined experimentally by shake flask method, high performance liquid chromatography. ## B. CHEMICAL PROPERTIES OF DRUG SUBSTANCES - A chemical property is a drugs property that becomes evident after a chemical reaction. Chemical properties are determined by the investigation of the chemical property. #### Major chemical properties that are studies in preformulation are:- - Hydrolysis - Oxidation and Reduction - Racemisation - Polymerisation ### I) HYDROLYSIS - Hydrolysis means the reaction of a drug molecule with water resulting in the cleavage of chemical bond. this leads to degradation of substance. - Esters, amides, lactums are most prone to hydrolysis. - Hydrolysis are of two types:- - Acid based hydrolysis - Base based hydrolysis - Water can act as both acid and base.  #### Acid based hydrolysis - In case of acid based hydrolysis, Water acts as a base. - Water becomes H₃O⁺ ion - Hydronium ion. - Taking an example of acetic acid. - CH₃COOH + H₂O → H₃O⁺ + CH₃COO- #### Base based hydrolysis - In case of base based hydrolysis, Water acts as a acid. - Water becomes proton donor, to be a Hydroxide ion (OH^-) - Taking an example of pyridine. #### Hydrolysis can be prevented by :- - Addition of buffers, addictives, surfactants - suppresses hydrolysis. - Modification of chemical structure. - Replacing aqueous solvents with non aqueous solvent - reduces hydrolysis. - Reduce exposure to water. - Conversion of some drugs into dry powder for reconstitution. - Examples of drugs that undergo hydrolysis - aspirin, penicillin, diamorphine, etc. ### II) OXIDATION AND REDUCTION - Oxidation and reduction are the common pathway for drug degradation in solid and liquid formulations. Oxidation and reduction involve the transfer of electrons, between the reactants. These two processes are together called Redox reactions. - Oxidation - loss of electrons - Reduction - gain of electrons - Generally, in pharmaceutical formulations, oxidation is mediated by the reaction with atmospheric oxygen. #### Oxidation occurs in two ways:- - Auto - oxidation - Free radical chain process #### Auto oxidation - Defined as reaction of substance with molecular oxygen, which produces free radical, by homolytic bond fission of a covalent bond. #### Free radical chain process - Occurs as 3 step process - initiation, propagation and termination. - During initiation, compound is converted to a free radical. - In propagation step, free radical combines with oxygen to form peroxy radical. - The peroxy radical further combines with hydrogen to form hydroperoxide and new radical is formed in the termination step. - Some radicals combine to form inactive products. #### Such a degeneration can be prevented by :- - Use of antioxidants and chelating agent. - Contact of drugs with heavy metals must be avoided. - Reducing agents can be used to prevent oxidation. - pH adjustment can be done to prevent oxidation and reduction - Oxygen in containers can be replaced with nitrogen or carbon dioxide. - Store in dark and cool containers. ### III) RACEMISATION - a process of conversion of optically active compound into an optically inactive compound.  - Half of the compound becomes its mirror images. - Rate of racemisation depends on the presence of catalytic hydrogen, hydroxyl ion, heat, light, temperature and solvent. - Interconversion can alter the pharmacokinetic properties, pharmacological properties, and toxological properties. - This conversion can make the drug inert or dangerous. - Eg. 1- epinephrine is 15-20 times active than the d-form. ### IV) POLYMERISATION - form of chemical degradation where two or more identical molecules combine to form large complex molecules known as polymers. - It can also be defined as a process in which simple monomer molecules combined to form large complex. #### Polymerisation can be of mainly two types:- - **Addictive polymerisation** - monomers with double or triple bond combine to form polymers, and the reaction does not give by products. - **Condensation polymerisation** - monomers combine to form polymers along with the formation of by products like water, ammonia, hydrochloric acid etc.  - Eg. - shellac on aging undergoes polymerisation which disintegration and dissolution time. - Glucose solution darkens due to polymerisation. - Formaldehyde solution, on standing, leads to formation of white deposit. ## BIOPHARMACEUTICAL CLASSIFICATION SYSTEM [BCS] OF DRUGS - BCS of drugs is a system to differentiate drugs on the basis of :- - Solubility - Permeability - Dissolution - Scientific framework for classifying drug substances based on their aqueous solubility and intestinal permeability. - A theoretical basis for correlating in-vitro drug dissolution with in-vivo bioavailability was developed. - The classification of drugs is based on Fick's first law :- - Fick's first law states, J_W = P_W * C_W. - J_W = drug flux across the gut wall. - P_W = permeability of the membrane. - C_W = drug concentration at GI membrane. ### SOLUBILITY - maximum amount of solute dissolved in a given solvent under standard conditions of temperature, pressure, and pH - measured to determine solubility. - solubility is the ability of the drug to be in solution after dissolution. ### PERMEABILITY - Ability of drug to pass the biological membrane which is lipophilic. - permeability of drug is indirectly based on the extent of absorption of a drug substance. - determined using the in situ method: rat intestinal perfusion method. ### DISSOLUTION - is a process in which solid substance solubilises in a solvent. - dtermined using UPS Apparatus I @ 100rpm or Apparatus II @ 50rpm. - dissolution media: 900ml - 0.1 N HCl, pH - 4.5 or 6.8 buffer, simulated intestinal fluid. ###### Apparatus 1 ###### Apparatus 2 | CLASS | SOLUBILITY | PERMEABILITY | EXAMPLES | |---|---|---|---| | CLASS I | HIGH | HIGH | METAPROLOL, PROPRANOLOL | | CLASS II | LOW | HIGH | NIFEDIPINE, NAPROXEN | | CLASS III | HIGH | LOW | CIMETIDINE, METFORMIN | | CLASS IV | LOW | LOW | TAXOL, CHLORTHIAZOL | ### CLASS I - Drug dissolves rapidly and absorbs rapidly. - Gives therapeutic action, shows excellent property. - Ideal for oral route of administration. ### CLASS II - Drugs dissolve slowly and absorb rapidly. - Optimum for controlled release drugs via oral or intravenous route of administration. - Dissolution is rate controlled. ### CLASS III - Drug dissolves rapidly but absorption is limited. - Bioavailability is incomplete. - Permeability is rate controlled. ### CLASS IV - Low dissolution rate and low permeability. - Slow therapeutic action. - Oral administration is not preferred. - Intravenous and other routes of administration is preferred. ## APPLICATIONS of BCS of DRUGS - Valuable tool for formulation scientist for selection of design of dosage form. - Reduce cost and time for scale-up and post-approval changes. - Applicable in clinical and pre-clinical testing. - Eliminates the need of human subjects to unnecessary drug exposure. - Helps in maintaining high public standard of therapeutic equivalence. ## APPROACHES TO BE MADE IN EACH CLASS OF BCS - CLASS I - Simple oral dosage form. - CLASS II - techniques to increase surface area, change solvents or surfactants. - CLASS III - incorporate permeability enhancers. - CLASS IV - combine approaches of class I & II. ## APPLICATION OF PREFORMULATION IN DIFFERENT DOSAGE FORMS AND IMPACT IN ITS STABILITY ### SOLID DOSAGE FORMS - Physicochemical properties and chemical properties are studied to determine the exact drug substance, excipients, manufacturing process etc to be used in the formulation. - Instability problem - change in therapeutic effect, release of drug from dosage form, manufacturing problems. ### LIQUID DOSAGE FORMS - Physicochemical properties like pH, colour, clarity, viscosity etc. - Chemical problems - assay, degradation product analysis, microbial properties determination. - Instability problems - loss of flavour, interaction with plastic bottles, settling, caking, and crystal growth, creaming, coalescence, breaking, flocculation, phase inversion. ### PARENTRAL DOSAGE FORMS - Physicochemical properties like bulk characterisation and solubility analysis. - Chemical problems - spectroscopical studies and chromatographic studies. - Instability problems - discolouration due to oxidation and photochemical reaction, presence of precipitate, formation of clouds due to chemical reactions, presence of crystals called whiskers at the tip of the container.