PREFORMULATION CONSIDERATION
Md. Imran Nur ManikLecturerDepartment of PharmacyPrimeasia University
Introduction to Preformulation
Preformulation is the branch of Pharmaceutical science that utilizes biopharmaceutical principles in the determination of physicochemical properties of the drug substance.
Prior to the development of any dosage form new drug , it is essential that certain fundamental physical & chemical properties of drug powder are determined .
This information may dictate many of subsequent event & approaches in formulation development.
This first learning phase is called as preformulation.
INTRODUCTION
DEFINITION:-Investigation of physico-chemical properties of the new drug compound that could affect drug performance and development of an efficacious dosage form”.
Requires to maintain Stability,Efficacy, Quantity,Bioavailability and Standards of Drug.
Objective of the Preformulation Considerationis
Objectives of the Preformulation Considerations are To provide and understand
The degradation process, Any adverse conditions relevant to the drug, Bioavailability, Pharmacokinetics and formulation of similar compound and Toxicity.
Usefulness of Preformulation ConsiderationisPreformulation influences aids in the
(a) Selection of the drug candidate itself,(b) Selection of formulation components, (c) API& drug product manufacturing processes, (d) Determination of the most appropriate container
closure system, (e) Development of analytical methods, (f) Assignment of api retest periods (g) The synthetic route of the api, (h) Toxicological strategy.
Drug Discovery Literature Search Preliminary Data• Stability assay• Key Stability Data• Key solubility Data
Molecular Optimization Salts & solvates Prodrugs
Evaluation & Selection of Drug
Formulation Request
Physical Characterization• Bulk properties• Solubility profile• Stability profile
Formulation Development• Compatibility & Stability• Dissolution• Bioavailability
Phase I Formulation• IND Stability• Bioavailability• Scale-up
Investigational New Drug (IND) Application
Process Research• Improve Yield• Alternate route• Produce bulk
Process Development• Bulk scale-up
Analytical Research• Assay development
Analytical Research• Bulk clearance• Toxicity potency• Formulation assay• IND formulation
stability
Bioavailability• In-vivo models
Toxicology• Acute• Chronic
Preliminary evaluation and molecular optimization
a) Compound identity.b) Formula and molecular weight.c) Structure. d) Therapeutic indications:
- Probable human dose. - Desired dosage form(s) - Bioavailability model - Competitive products
Contd…
e) Potential hazardsf) Initial bulk lots: - Lot number - Crystallization solvent(s) - Particle size range - Melting point - % volatilesg) Analytical methods: - HPLC assay - TLC assay - UV/ Visible spectroscopy
Contd…8
Preliminary Evaluation
ORGANOLEPTIC PROPERTIES
COLOR ODOUR TASTE
OFF-WHITE PUNGENT ACIDIC
CREAM-YELLOW SULFUROUS BITTER
SHINY FRUITY SWEET
AROMATIC TASTELESS
ODOURLESS TASTELESS
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Factors determining the activity of drugsA large number of factors play their roles in
determining the activity of a drug. Thus successful integration of these factors results in successful drug therapy.
These factors include1. Physico-chemical characteristics of the drug2. Physicochemical Characteristics of dosage
form3. Characteristics of the biological system
involved4. Other factors
Physico-chemical characteristics of the drug
These includes
a) Solubility of the drug and its dissolution rate,b) Particle size and effective surface area,c) Plymorphism, Amorphism,Pseudopolymorphismd) Salt form of the drug,e) Lipophilicity of the drug,f) Drug pKa & pH,g) Drug Stability.
Physicochemical Characteristics of dosage formIt encompasses
a) Disintegration time,b) Dissolution time,c) Manufacturing variation,d) Nature and Type of dosage form,e) Product age and Storage conditionf) Pharmaceutical ingredients.
Characteristics of the biological system involved
Generally four types of biological factors are involved. They are as follow
I. Absorption Related Factors: Which includes a) Route of drug administration,b) Gastric Empting time,c) Intestinal transit time,d) Interaction of Drug with the components of GIT.e) Protein binding
II. Dissolution Related Factors: This Include
a) Lipid Solubilityb) Membrane permeabilityc) Enterohepatic cycling III. Biotransformation related factors: This Includes
d) Biological half lifee) Pre-systemic Metabolism at luminal gut wallf) Hepatic Tissue Protrusiong) Genetic effect
IV. Excretion related factors: This Includes
a) Glomerular Filtrationb) Drug interaction
Other factorsThere are some other types of factors which includesI. Individual Factors: This Includesc) Aged) Sexe) Body weightf) Dietg) Pregnancy
II. Pharmacologic Factors: This Includesa) Log dose Responseb) Drug receptorc) Drug interactiond) Drug Concentratione) Drug binding competitionf) Synergism
III. Clinical effect: This Includesg) Placebo Effecth) Concurrent diseasei) Precision in diagnosis
Characterization of an unidentified chemical with major three parameters is called bulk characterization.
It is required to avoid misleading in the prediction of stability or solubility which depends on particular crystal form.
It encompasses
Bulk CharacterizationCrystallinity and polymorphismHygroscopicityFine particle characterizationBulk densityPowder flow properties
Bulk characterization
Solubility analysisa) Ionization constant- pKab) pH Solubility profilec) Common ion effectd) Thermal effectSe) Solubilizationf) Partition co-efficientg) Dissolution Stability analysish) Stability in toxicology formulationsi) Solution state stability
pH rate profilec) Solid state Stability
Bulk stability Compatibility
POWDER FLOW PROPERTIES
Powder flow properties can be affected by change in particle size, shape & density.
The flow properties depends upon following-1. Force of friction.2. Cohesion between one particle to another.
Fine particle posses poor flow by filling void spaces between larger particles causing packing & densification of particles..
By using glident we can alter the flow properties. e.g. Starch, Talc.
Determination of Powder Flow Properties By determining Angle Of
Repose. It is a maximum angle
between the surface of a pile of powder & horizontal plane.
A greater angle of repose indicate poor flow.
It should be less than 30°. & can be determined by following equation.
tan θ = h/r. where, θ = angle of
repose. h=height of pile. r= radius.
Angle Of Repose
( In degree)
Type Of Flow
<25 Excellent
25-30
Good
30-40 Passable
>40 Very poor
Angle of Repose
It is a maximum angle between the surface of a pile of powder & horizontal plane.
Angle of repose is measured by the equation: tanθ=h /r here, h=height of conical heap & r=radius of horizontal plane of powder
Determination of Powder Flow Properties
Measurement of free flowing powder by compressibility.
Also known as Carr's index.
CARR’S INDEX(%) =(TAPPED DENSITY – POURED DENSITY) X 100 TAPPED DENSITY
It is simple, fast & popular method of predicting powder flow characteristics.
Determination of Powder Flow Properties
Carr’s Index Type of flow 5-15 Excellent
12-16 Good
18-21 Fair To Passable
23-35 Poor
33-38 Very Poor
>40 Extremely Poor
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Particle size can influence variety of important factors :
- Dissolution rate- Suspendability- Uniform distribution- Penetrability- Lack of grittiness
PARTICLE SIZE
PARTICLE SHAPEParticle shape will influence the surface area, flow of particles, packing & compaction properties of the particles.
Cont…
Plasma Level Time Curve
It is a graph depicting drug concentration in plasma as a function of time after dosing.
The plasma level time curve is generated by obtaining the drug concentration in plasma samples taken at various time intervals after a drug product is administered.
General description: The concentration of drug in each plasma sample is plotted on rectangular-coordinate graph paper against the corresponding time at which the plasma sample was removed. As the drug reaches the general (systemic) circulation, plasma drug concentrations will rise up to a maximum. Usually, absorption of a drug is more rapid than elimination. As the drug is being absorbed into the systemic circulation, the drug is distributed to all the tissues in the body and is also simultaneously being eliminated. Elimination of a drug can proceed by excretion, biotransformation, or a combination of both.
Terminologies:MSC (MTC): Maximum safe Concentration( Minimum Toxic Concentration) is the concentration of drug in plasma above which side effect or toxic effect of drug occurs in patient.MEC: Minimum Effective Concentration reflects the minimum concentration of drug needed at the receptors to produce the desired pharmacologic effect. Onset of Action: The onset of action corresponds to the time required for the drug to reach the MEC.Duration of drug action: The duration of drug action is the difference between the onset time and the time for the drug to decline back to the MEC.Cmax: It is the maximum drug concentration in the plasma.
tmax: The time of peak plasma level is the time required to achieve the maximum drug concentration in the plasma .The intensity of Action: It is the measurement of the pharmacologic response of the drug. Generally the higher the plasma drug concentrations the greater the pharmacologic response, which reaches up to a maximum.Duration of Drug Action: The duration of drug action is the difference between the onset time and the time for the drug to decline back to the MEC.
Dissociation (or ionization) constants and pKa
Many drugs are either weak acids or weak bases. In solutions of these drugs equilibria exist between undissociated molecules and their ions. Thus, in a solution of a weakly acidic drug HA the equilibrium may be represented by Eqn 1:
HA H++A- ……………………….(1)
Similarly, the protonation of a weakly basic drug B can be represented by Eqn 2:
--------------------------------------------------(2)
In solutions of most salts of strong acids or bases in water, such equilibria are shifted strongly to one side of the equation because these compounds are completely ionized.
The ionization constant (or dissociation constant} Ka of a weak acid can be obtained by applying the Law of Mass Action to Eqn 1 to yield:
----------------------------------------------(3)
Taking logarithms of both sides of Eqn 3 yields:
log Ka = log [H+] + log [A-] - log [HA]
The signs in this equation may be reversed to give:
-log Ka = -log [H+] - log [A-] + log [HA] -------------------------------------(4)
The symbol pKa, is used to represent the negative logarithm of the acid dissociation constant Ka in the same way that pH is
used to represent the negative logarithm of the hydrogen ion concentration, and Eqn 4 may therefore be rewritten as:
pKa = pH + log [HA] - log [A-]
or,
----------------------------------------------------------(5)
A general equation may be written that is applicable to any acidic drug with one ionizable group, where Cu and Ci represent the concentrations of the unionized and ionized species, respectively.
This is known as the Henderson--Hasselbalch equation, (Eqn 6):
-----------------------------------------------------------------------(6)
The Henderson-Hasselbalch equation for any weak base with one ionizable group may therefore be written as:
Or where ci and cu refer to the concentrations of the protonated and unionized species, respectively.
Crystallinity and polymorphismDepending on internal structure compounds is classified as
1. Crystalline 2. Amorphous
Crystalline materials are those in which the molecules are packed in a defined order, and this same order repeats over and over again throughout the particle.Crystalline compounds are characterized by repetitious spacing of constituent atom or molecule in three dimensional array.In amorphous form atom or molecule are randomly placed.
Solubility & dissolution rate are greater for amorphous form then crystalline, as amorphous form has higher thermodynamic energy.
Eg. Amorphous form of Novobiocin is well absorbed whereas crystalline form results in poor absorption.
CrystallinityCrystal habit & internal structure of drug can affect bulk & physicochemical property of molecule.
Crystal habit is description of outer appearance of crystal.
Internal structure is molecular arrangement within the solid. Change with internal structure usually alters crystal habit.
Eg. Conversion of sodium salt to its free acid form produce both change in internal structure & crystal habit.
Different shapes of crystals
Techniques for studies of crystalsMicroscopyHot stage microscopyThermal analysisX-ray diffraction
Polymorphism
It is the ability of the compound to crystallize as more than one distinct crystalline species with different internal lattice.
Different crystalline forms are called polymorphs.
Polymorphs are of 2 types 1. Enatiotropic 2. Monotropic
Polymorphism
The polymorph which can be changed from one form into another by varying temp. or pressure is called as Enantiotropic polymorph.
Eg. Sulfur.
One polymorph which is unstable at all temp. & pressure is called as Monotropic polymorph. Which means that only one polymorphic form is stable and any other polymorph that is formed will eventually convert to the stable form.
Eg. Glyceryl stearate.
PolymorphismPolymorph differ from each other with respect to their physical property such as
Solubility (the stable polymorphic form will have the slowest dissolution rate)
Melting point Density Hardness Compression characteristic
During preformulation it is important to identify the polymorph that is stable at room temp.
Eg. 1)Chloromphenicol exist in A,B & C forms, of these B form is more stable & most preferable. 2)Riboflavin has I,II & III forms, the III form shows 20 times more water solubility than form I.
Hygroscopicity
A substance that absorbs sufficient moisture from the atmosphere to dissolve itself is known as a hygroscopic or deliquescent materials.
For this reason pharmaceutical air conditioning is usually set below 50% RH, and very hygroscopic products, e.g. effervescents, which are particularly moisture sensitive, are stored and made below 40% RH.
Solubility analysisA solution may be denned as a homogeneous mixture of two or more components that form a single phase .The component that determines the phase of the solution is termed the solvent and usually constitutes the largest proportion of the system. The dispersed as molecules or ions throughout the solvent are termed solutesThe transfer of molecules or ions from a solid state into solution is known as dissolution. The extent to which the dissolution proceeds under a given set of experimental conditions is referred to as the solubilityof the solute in the solvent.
Aqueous solubility: Dictates the ease with which formulations for oral gavage and intravenous injection studies in animals are obtained.
Intrinsic solubility (C0): Dictates the fundamental solubility when completely unionized.
In many instances, dissolution rate in the fluids at the absorption site is the rate limiting step in the absorption process.Dissolution rate can affect
- Onset of action.- Intensity of action.- Duration of response.- Control the overall Bioavailability of drug
form.
The solubility should ideally be measured at twotemperatures:
1. 4°C to ensure physical stability and extend short-term storage and chemical stability until more definitive data are available. The maximum density of water occurs at 4°C.This leads to a minimum aqueous solubility.2. 37°C to support biopharmaceutical evaluation.
Addition of co-solvent pH change method Reduction of particle size Temperature change method Hydotrophy Addition of Surfactant Dielectrical Constant Complexation
General Method of Increasing the Solubility
DISSOLUTION
An equation known as the Noyes-Whitney equation was developed to define the dissolution from a single spherical particle. The rate of mass transfer of solute molecules or ions through a static diffusion layer (dm/dt) is directly proportional to the area available for molecular or ionic migration (A), the concentration difference (∆C) across the boundary layer, and is inversely proportional to the thickness of the boundary layer (h).
SOLUBILIZATION“ Solubilization is defined as the spontaneous passage of poorly water soluble solute molecules into an aqueous solution of a soap or detergent in which a thermodynamically stable solution is formed ”.
It is the process by which apparent solubility of an otherwise sparingly soluble substance is increased by the presence of surfactant micelles .
Process Of Solubilization
The process of solubilization involves the breaking of inter-ionic or intermolecular bonds in the solute, the separation of the molecules of the solvent to provide space in the solvent for the solute, interaction between the solvent and the solute molecule or ion.
Step 1: Holes opens in the solvent
Step2: Molecules of the solid breaks away from the bulk
Step 3: The free solid molecule is intergraded into the hole in the solvent
Process Of Solubilization
DESCRIPTIVE SOLUBILITIESDescription Parts of solvent required for
one part of solute
Very soluble < 1 Freely soluble 1 - 10
Soluble 10 - 30 Sparingly soluble 30 - 100 Slightly soluble 100 - 1000
Very slightly soluble 1000 - 10,000
Insoluble > 10,000
Aqueous concentrates of volatile oils can be prepared by solubilization.
Example: soaps used for solubilising phenolic
compounds for use as disinfectants- Lysol, Roxenol etc.
Barbiturates, anticoagulant, alkloidal drugs are dissolved with polysorbate by solubilization.
Applications of solubilization
Thermal AnalysisIt is used to study the physico-chemical interactions of two or more components.Differential thermal analysis (DTA):DTA measures the temperature difference between the sample and a reference as a function of temperature or time when heating at a constant rate.Differential scanning calorimetry (DSC): It measures the enthalpy of transition
Effect of temperature on the solubility of drug can be determined by measuring heat of solution. (∆Hs).
ln S = -∆Hs/RT + C. where, S = Molar solubility at temperature T
(K). R = Gas constant.
Heat of solution represents the heat released or absorbed when a mole of solute is dissolved in a large quantity of solvent.
Mostly solution process is endothermic (∆Hs = +ve) & thus increasing the solution temperature increase the drug solubility.Typical temp. range should include 5°C, 25°C, 37°C & 50°CImportance: Determination of temperature effect on solubility helps in predicting storage condition & dosage form designing
Partition CoefficientPartition coefficient is generally defined as the fraction of drug in an oil phase to that of an adjacent aqueous phase.P o/w = (C oil / C water) equilibriumAccordingly compounds with relatively high partition coefficient are predominantly lipid soluble and consequently have very low aqueous solubility. Compounds with very low partition coefficients will have difficulty in penetrating membranes resulting poor bioavailability.
MEASUREMENT OF PARTITION COEFFICIENT:
It can be measured by using following methods.
Shake flask (or tube) method.
HPLC method.
Electrochemical method.
Slow-Stirring Method.
Estimation method based on individual solubilities.
COMMON ION EFFECT
The common-ion effect is a term used to describe the effect on a solution of two dissolved solutes that contain the same ion.
Common-ion effect
The common-ion effect is used to describe the effect on an equilibrium involving a substance that adds an ion that is a part of the equilibrium. Adding a common ion prevents the weak acid or weak base from ionizing as much as it would without the added common ion.
A common ion often significantly reduces the solubility of a slightly soluble electrolyte.
Common-ion effectFor example, silver chloride, AgCl, is a slightly soluble salt that in solution dissociates into the ions Ag+ and Cl - , the equilibrium state being represented by the equation AgClsolid Ag⇒ ++Cl -
According to Le Châtelier's principle, when a stress is placed on a system in equilibrium, the system responds by tending to reduce that stress. If another solute containing one of those ions, e.g., sodium chloride, NaCl, is added which supplies Cl - ions, the solubility equilibrium of the solution will be shifted to remove more Cl - from the solution i.e. right to left by forming more solid AgCl. The net result is the decrease in the solubility of AgCl.
Addition of common ion reduces the solubility of slightly soluble electrolyte.The “salting out” results from the removal of water molecules as solvent due to the competing hydration of other ions.So weakly basic drug which are given as HCl salts have decreased solubility in acidic solution.
E.g. Chlortetracycline, Papaverine, Bromhexine, Triamterene, etc.The reverse process “salting in” arises with larger anions. (E.g. Benzoate, salicylate) which can open the water structure.These hydrotropes increase the solubility of poorly water soluble compounds
STABILITY ANALYSIS
Why Stability?Provide a evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as….. temperature, Humidity and light.
Establish a re-test period for the drug substance or a shelf life for the drug product and recommended storage conditions.
Because physical, chemical or microbiological changes might impact the efficiency and security of the final product
Where and Why?Stability Studies are preformed on ...• Drug Substances (DS) The unformulated drug
substance that may subsequently be formulated with excipients to produce the dosage form.
• Drug Products (DP) The dosage form in the final immediate packaging intended for marketing…….
Development of a drug substance into a suitable dosage form requires the Preformulation stability studies of drug under the following categories:-
[1] Solid state stability.[2] Solution state stability
1] Solid state stability• Solid state reactions are much slower & more
difficult to interpret than solution state reactions because of reduced no. of molecular contacts between drug & excipient molecules & occurrence of multiple reactions.
Techniques for solid state stability studies:Solid State NMR Spectroscopy. (SSNMR)Powder X-ray diffraction. (PXRD)Fourier Transform IR. (FTIR)Raman Spectroscopy.Differential Scanning Calorimetry (DSC).
[2] Solution State Stability• The primary objective is identification of conditions
necessary to form a solution.• These studies include the effects of- pH - Temperature. - Light - Oxygen. - Cosolvents - Ionic Strength.- Solution Stability investigations usually commence
with probing experiments to confirm decay at the extremes of pH & temperature.
- If the results of this solution stability studies dictate the compound as sufficiently stable, liquid formulation can be developed.
What are changes?Physical changes
• Appearance • Melting point • Clarity and color of solution • moisture • Crystal modification (Polymorphism) • Particle size
Chemical changes • Increase in Degradation • Decrease of Assay
Microbial changes
Forced degradation studiesAcidic & Basic conditions.
Dry heat exposure
UV radiation exposure
Influence of pH
Influence of temperature
Influence of ionic strength
Chemical degradation studies
Hydrolysis
Oxidation
Reduction
Decarboxylation
Photolysis
Testing scope for Solid dosage
Physical-chemical properties – Appearance – Elasticity – Mean mass – Moisture – Hardness – Disintegration – Dissolution
Chemical properties – Assay – Degradation
Microbial properties
Container closure system properties – Functionality tests (e.g. extraction from blister)
Tablet & Capsule
Testing scope for Oral liquid form
Physical-chemical properties – pH – Color & clarity of solution – Viscosity – Particle size distribution (for oral suspensions only)
Chemical properties – Assay – Degradation products – Degradation preservatives – Content antioxidants
Microbial properties
Container closure system properties – Functionality tests
Testing scope for LIQUID FORMS for inj. and PARENTRAL
Physical-chemical properties – pH – Loss on weight – Color & clarity of solution
Chemical properties – Assay – Degradation products – Degradation preservatives – Content antioxidants
Microbial properties
Container closure system properties – Functionality tests
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