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preformulation

The document discusses preformulation studies for a new drug entity. It defines preformulation studies as investigations of a drug substance's physical and chemical properties alone and with excipients to develop a safe, effective, and stable dosage form. The objectives are to establish physico-chemical parameters, determine kinetics and stability, and establish compatibility with excipients. Key aspects discussed include stability studies, physicochemical properties, drug-excipient interactions, and analytical techniques to detect interactions like DSC and TLC.

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MORDEN PHARMACEUTICES PREFORMULATION STUDIES SUBMITTEDto, dr.amsa p professor DepARTMENT of pharmaceutices BY, MOHAN KUMAR P M.PHARM 1ST SEMESTER
Definition: It can be defined as an investigation of physical and chemical properties of a drug substance alone and or when combined with excipients in order to develop safe, effective and stable dosage form. Objectives: • To establish the physio-chemical parameters of a new drug entity. • To determine its kinetics and stability. • To establish its compatibility with common excipients. • It generates useful information to the formulator to design an optimum drug delivery system.
CONCEPT • Prior to the development of these major dosage forms, it is essential that certain fundamental, physical and chemical properties of drug molecule and other properties of drug powder are determined. This information decides many of the subsequent events and approaches in formulation development.
STABILITY a.Solid state temperature, light, humidity b.Solution Solvent, pH, light PHYSIOCHEMICAL PROPERTIES Molecular structure and weight Color, odour Particle size, shape, crystanility Melting point Thermal analysis profile DTA, DSC, TGA
Hygroscopicity Asorance spectrum UV , IR Solubility Partition co efficient Polymorphism potential PHYSIO MECHANICAL PROPERTIES bulk and tapped density Compressibility IN VITRO AVAILIBILITY PROPERTIES Dissolution of drug crystals, drug pellet OTHERS - PPB, Kinetics study
Stability analysis: 1. Solution stability, 2. pH rate profile, 3. Solid state stability, 4. Bulk stability, 5. Stability in toxicology formulation.
DRUG EXCIPIENT INTERACTIONS • Excipients play an important role in formulating a dosage form. • Excipients are ingredients which along with active pharmaceutical ingredients makeup the dosage forms. • Excipients act as protective agents ,bulking agents and can also be used to improve bioavailability of drug. • Excipients as like other active pharmaceutical ingredients need to be stabilized and standardized. EXCIPIENT: An excipient is a substance formulated alongside the active ingredient of a medication ,included for the purpose of long term stabilization,bulking up solid formulations that contain potent active ingredients in small amounts.
Excipients used as carriers for active ingredients are • Binders • Disintegrants • Fillers(diluents) • Lubricants • Glidants • Compression aids • Colors • sweeteners • Preservatives • Flavors • Film formers/coatings • Surfactants • Anti adherents • Antioxidants • Humectants
Drug excipient interaction: In pharmaceutical dosage forms the active pharmaceutical ingredients are in intimate contact with the excipient which are greater quantity excipient and drugs may have certain incompatibility which lead to drug excipient interaction. Types of drug excipient interactions:  Physical interactions  Chemical interactions  Biopharmaceutical interactions  Excipient- excipient interactions
Physical interactions: • Physical interactions alter the rate of disssolution, dosage uniformity,etc., • They are quite common but are difficult to detect. • A physical interaction doesn‘t involve any chemical changes. • Physical interactions are frequently used in the manufacturing of dosage forms, for example, to modify drug dissolution. • Many of such interactions can be categorized as noncovalent. These may include vanderWaals attractions (or dispersion forces), hydrogen bonding, and electrostatic interactions(also called ionic bonding). All of these interactions involve an electrical chargedue to temporary dipoles or ion formation.
Interactions Complexation: • Usually binds reversibly with drugs to form complex. • Insoluble complexes are formed which lead to slower dissolution. • Decreased adsorption of drug. Beneficial effect examples: • Cyclodextrin is often used to improve bioavailability of poorly water soluble drugs. • This increases bioavailability and increases rate. Detrimental effect examples: tetracycline formed insoluble complex with calcium carbonate leading to slower dissolution and decreased absorption.
Chemical interactions: • Active pharmaceutical ingredients and excipients react with each other to form unstable compounds. Oxidation and the role of excipients: • Oxidation is broadly defined as loss of electrons in a system, but it can be restated as an increase in oxygen or a decrease in hydrogen content. • Oxidation always occurs in tandem with reduction;the so called REDOX reaction couple. • It can be defined as the loss of electron positive atom, radical or electron, or the addition of an electronegativite moiety. • Oxidation reaction can be catalysed by heavy metals, light, leading to free radical formation. Free radical then react with oxygen to form peroxy radicals.
Biopharmaceutical interactions:  These are the interactions which are observed after administration of medicine.  These interactions occur in the form of:  The interaction is between the medicine (drug substance and excipients) and the body fluids.  The interaction have the tendency to influence the rate of absorption of drug.
Various e.g. of these interactions are as :  remature breakdown of enteric coat- Enteric coating polymers e.g, cellulose acetate phthalate and hydroxyl propyl cellulose acetate phthalate, Dissolve prematurely in the stomach in the presence of antacids or drugs. cause increase in the pH of the stomach cause premature release of API in stomach itself,which results in degradation of drug in stomach. e.g.,side effects like gastric bleeding as in the case of NSAIDs.
Excipient- excipient interactions: • This type of interaction occurs between two or more excipient in a drug molecule. • Ex:in proper addition of electrolyte such as calcium or magnesium ion in suspension containing NaCMC which will cause formation of calcium or magnesium CMC. • The suspending agent will be destroyed and cannot perform it’s function.
ANALYTICAL TECHNIQUES USED TO DETECT DRUG-EXCIPIENT INTERACTIONS: 1. Thermal methods- DSC-Differential Scanning Calorimetry DTA-Differential Thermal Analysis Isothermal micro calorimetry Hot stage microscopy 2.Spectroscopic techniques- FT-IR spectroscopy Powder X-ray diffraction Solid state NMR 3.Chromatography- SIC-Self interactive chromatography TLC-Thin layer chromatography HPLC-High pressure liquid chromatography 4.Accelerated stability study 5.Miscellaneous-Radiolabelled techniques Fluorescence spectroscopy
DSC-Differntial Scanning Calorimetry DSC is widely used technique to predict any interaction involving thermal changes. METHOD: • The preformulation screening of drug–excipient interaction requires (1:1) Drug:excipient ratio, to maximise the likehood of observing an interaction. • Mixture should be examined under N2 to eliminate oxidative and pyrrolytic effects at heating rate (2,5 or 100c/min) on DSC apparatus. Interaction detected: • Elimination of endothermic peak. • Any new peak appeared. • Change in melting point/ peak temperature.
DTA-Differential Thermal Analysis • This technique is useful for identifying and quantitatively analyzing the chemical composition of substances by observing the thermal behaviour of a sample as it is heated. • In this change in temperature between test sample and reference material is measured under controlled and identical condition. • This differential temperature is plotted against time or temperature. • Interaction can be identified by comparing DTA curve obtained from the test sample with those of reference material.  If any interaction occur-thermogram (DTA curve) of a mixture show appearance or disappearance of one or more peaks corresponding to those of the components.  If no interaction occur- the thermogram of mixtures show same patterns corresponding to those of the individual components.
TLC AND HPTLC  TLC is generally use as confirmative test of compatibility after performing DSC because if sample undergo negligible thermal changes,it will difficult by thermal method.  Method-stationary phase consist of powder(silica, alumina, polyamide, cellulose,etc.) adhered onto glass, plastic or metal plate.  Solution of drug,excipient and drug : excipient mixture are prepared and spotted on the same baseline at the end of the plate.  The plate is then placed upright in a closed chamber containing the solvent which constitutes the mobile phase.  Any change in chromatograph such as appearance of a new spot or a change in Rf values of component is indicative of an interaction.
RADIO LABELLED TECHNIQUES  It is important when the API is having radio-activity.  Method is carried out by using either 3H or 13C.  Highly sensitive method but the cost of carrying out the method and bioavailability of well established other techniques and methods ,this method is generally not preferred.
KINETICS OF STABILITY  Drug stability means the ability of the pharmaceutical dosage form to maintain the physical,chemical, therapeutic and microbial properties during the time of storage and usage by the patient.  Stability is defined as the capacity of drug substance to remain within the established specification to maintain its identity, strength, quality and purity throughout the retest or expiration during period.  Chemical kinetics is the study of rate of chemical changes taking place during the chemical reaction.  It determines stability of drug/ half life of the drug which is defined as time necessary for a drug to decay to its half life or 50% conc.
Rate and order of reaction  The velocity with which a reaction or a process occurs is called as its rate,  concentration of drugs which influences the rate of reaction or process is called as the order of reaction or order of process.  Consider the following chemical reaction Drug A Drug B  The rate of forward reaction is expressed as: -dA/dt -ve sign =concentration of drugs A decreases with time.  As the reaction proceeds,the concentration of the drugs B increases and the rate of reaction can also be expressed as :  dB/dt
 Experimentally the rate of reaction is determined by measuring the decrease in concentration if drug A with time.  If c is the concentration of drug A , the rate of decrease in c of drug A as it is changed to B can be described by expression as function of time t. dC/dt=-kc Where, k=rate constant n=order of reaction if, n=0 (zero order process) n=1 ( first order process)
• The three commonly encountered rate process: zero order reaction first order reaction mixed order reaction Zero order kinetics: • It is also called as constant rate process. • The reaction is said to be zero-order reaction, if the rate of reaction is independent of the concentration i.e.the rate of reaction cannot be increased further by increasing the concentration of reactants. dc/dt = -KoCo =-Ko equation….1 Where KO=zero-order rate constant ( in mg/min ) Rearrangement of eqn 1 yields: dc=-Kodt equation…….2
Integration of equation 2 gives: C-Co = -kot where, Co=concentration of drug at t=0, and C = concentration of drug yet to undergo reaction at time t.
First order kinetics: whose rate is directly proportional to the concentration of the drugs undergoing reaction i.e. greater the concentration , faster the reaction. First –order process is said to follow linear kinetics dC /dt = -K C where K= first –order rate constant (per hour) Graph showing linear relationship between rate of reaction and concentration of drug.
Factors affecting rate of reaction • Temperature • Light • Solvent • Surface area • Catalysis • Concentration • Dielectric constant
STABILITY TESTING Stability: defined as capability of a particular formulation in a specific container/ closure system to remain within its physical, chemical, microbilogical, toxicological, protective and informational specifications. • It is the extent to which a product retains, within the specified limits, throughout its period of storage and use, the same properties and characteristics possessed at the time of its packaging. Scope : • Provide evidence as to how the quality of drug product varies with time. • Establish shelf life of drug product. • Determines recommended storage conditions.
Stability testing methods 1. Real time stability testing 2. Accelerated stability testing 3. Retained sample stability testing 4. Cyclic temperature stress testing
REAL TIME STABILITY TESTING • Performed for longer duration of the test period in order to allow significant product degradation under recommended storage conditions. • Depends upon the stability of the product which should be long enough to indicate clearly that no measurable degradation occurs. Data collected at to distinguish stability of reference Appropriate instability from material include the frequency day to day stability of reagent as well as consistency performance
ACCELERATED STABILITY TESTING • A product is stressed at several high temp and the amount of heat input required to cause product failure is determined. • This is done to subject the product to a condition that accelerates degradation. • This information is then projected to predict shelf life or used to compare the relative stability of alternative formulations. Samples subjected Refrigerated Assayed to stress simultaneously The concept of accelerated stability testing is based upon Arrhenius equation, ln K = lnA + E ` RT
RETAINED SAMPLE STABILITY STUDY • Usual practice for every marketed product for which stability data are required. • Only one batch a year are selected. • If the number of batches marketed exceeds 50, stability samples from two batches are recommended to be taken. • Stability testing by evaluation of market samples is a modified method which involves taking samples already in the market place and evaluating stability attributes.
CYCLIC TEMPERATURE STRESS TESTING • Is not a routine testing method for marketed products. • In this method, cyclic temp.stress tests are designed on knowledge of the product so as to mimic likely conditions in market place storage. • The period of cycle mostly considered is 24 hours. • The min and max. temp for the cyclic stress testing is recommended to be selected on a product by product basis and considering factors like recommended storage temp for the product. • The test should normally have 20 cycles.
THEORIES OF DISPERSION  Dispersed system consist of particulate matter, known as the dispersed phase,distributed throughout a continuous or dispersion medium.  The dispersed material may range in size from particles of atomic and molecular dimensions to particles whose size is measured in millimetres.
Solid dispersion system • Solid despersion is defined as the despersion of one or more active ingridennts in an inert carrier or matrix at solid state prepared by melting solvent or melting solvent method. • 1. MOLECULAR DIFFUSION- obeys ficks law and second law of diffusion • 2. ficks first law relates diffusive flux to concentration under the assumption of stedy state. • J= -D ds/dx • J=FLUX, D=diffusion, S= concentration
• C. Ficks second law predicts how diffusion causes the concentration to change with time . It is partial differential equation which in one dimension reads dY/dt=D d2y/d2X t= time in sec D= diffusion coefficent in dimensions X= position
MECHANICAL DISPERSION Because of the variation in microscopic velocity within each flow channel from one channel to another spreading is present. EDDY DIFFUSION; the mixing process that is due to the random flucuation of fluid mass or the occurance of eddies in condition described as turbulent flow , exist in porous media in slight extent more in large particles.
MIXING DUE TO STRUCTURAT CONTROL The apparent mixing mechanism due to large scale structural variations in the granular material these variation scontrol the direction of movement of a given fluid partice, hence , if average concentration is taken along a given plane parallel or transverse to the direction of flow a large scale mixing is observed
ADSORPTION A process which differs the others in the amount of mass transported depends on the physiochemical interaction of the transported substance and the solid of the medium. The existane of an unbalanced force field causes migration of a liquid- borne contaminat from the liquid to the solid surface whereas in others it moves continuously from liquid to solid or vice versa.