1.preformulation concept in Modern pharmaceutics.pptx

Preformulation is topic in Modern pharmaceutics M.pharmacy.

1. MODERN PHARMACEUTICS a. Preformulation Concepts – Drug Excipient interactions - different methods, kinetics of stability, Stability testing. Theories of dispersion and Pharmaceutical Dispersion (Emulsion and Suspension, SMEDDS). Preparation and stability of Large and small volume parental – physiological and formulation consideration, Manufacturing and evaluation. b. Optimization techniques in Pharmaceutical Formulation : Concept and parameters of optimization, Optimization techniques in pharmaceutical formulation and processing. Statistical design, Response surface method, Contour designs, Factorial designs and application in formulation 2 Validation : Introduction to Pharmaceutical Validation, Scope & merits of Validation, Validation and calibration of Master plan, ICH & WHO guidelines for calibration and validation of equipments, Validation of specific dosage form, Types of validation. Government regulation, Manufacturing Process Model, URS, DQ,IQ, OQ &P.Q. of facilities.

2. 3 cGMP & Industrial Management : Objectives and policies of current good manufacturing practices, layout of buildings, services, equipments and their maintenance Production management: Production organization, , materials management, handling and transportation, inventory management and control, production and planning control, Sales forecasting, budget and cost control, industrial and personal relationship. Concept of Total Quality Management 4 Compression and compaction : Physics of tablet compression, compression, consolidation, effect of friction, distribution of forces, compaction profiles.Solubility . 5 Study of consolidation parameters ; Diffusion parameters, Dissolution parameters and Pharmacokinetic parameters, Heckel plots, Similarity factors – f2 and f1, Higuchi and Peppas plot, Linearity Concept of significance, Standard deviation , Chisquare test, students T-test , ANOVA test. 10 Hrs 10 Hr

3. PREFORMULATION

4. It is defined as phase of research and development in which preformulation scientist characterize physical & chemical properties of new drug molecule in order to develop safe, effective, and stable dosage form. Investigation of physical & chemical properties of a drug and mixer of drug & excipient 3

5. DEFINITION It can be defined as an investigation of physical and chemical properties of a drug substance - alone and or when combined with excipients . The overall objective of preformulation testing is to generate information useful to the formulator in developing stable and safe dosage forms with good bioavailability.

6. Prior to development of dosage form with new drug candidate, it is essential that some fundamental physicochemical properties of new drug molecule are to be determined . Th is information may dictate many of subsequent event s and possible approaches in formulation development .

7. To formulate an innovative,elegant, safe, efficacious dosage form which is capable of delivering the substances for its intended use. To formulate new dosage form of already existing drug. Determination of all the properties of drug and the best suitable dosage form for the drug molecule. The major goal of preformulatoin is to gather data, Which will permit the rational development of safe and efficacious dosage form..

8. DIRECT BENEFITS Gives direction for development of formulation in choice of dosage form,excipients,composition,physical structure. Helps i n ad j ust m ent of Phar m a c o k i net i cs and biopharmaceutical properties. S u p p ort f or p r ocess d e vel o pm e nt o f d r ug s u b s t ance (yield,filtration..). Produce nece s s a ry a n d use f ul d ata f or d e vel o pm e nt of analytical methods. 6

9. Receive new drug substance Obtain all available information If not available, do the literature search. Determine physical property of the new API. Macroscopic and Microscopic examination Determine polymorphs, solvates and hydrates . Stability testing at normal and exaggerated condition . Determine their solubility, partition co- efficient, pKa, dissolution rate. If poor bioavailability test results due to solubility, pKa, P, etc. make new salt or ester If satisfactory Check lot to lot uniformity Select most stable, active form for bioavailability testing. Check API stability w ith excipients Prepare worksheet and final preformulation report and issue to product development dept .

10. 9 I. PHYSICAL CHA R ACTERISTICS A. BULK CHARACTERISTIC Particle Size & Surface Area. Polymorphism. Crystallinity. Hygroscopicity. Flow properties & Bulk density. Compressibility. Drug-Excipient Compa ta bility . Electrostatic charge. Osmolarity. Rheology. Wettability.

11. 10 B . SOL U BILITY A N A L Y S IS 1) Aqueous Solubility . Intrinsic solubility. Ionization constant. Solubilization. Partition Coefficient. Thermal effect. Common ion effect. Dissolution . C . STABILITY ANALYSIS Solid State Stability. Solution State Stability.

12. 11 II. C H EMI C AL CHA R A C TER I STIC Oxidation. Hydrolysis. Photolysis. Racemization. Polymerization. Isomerization. Decarboxylation. Enzyme Decomposition .

13. “ When we mix two or more API and / or excipient with each other & if they are antagonistic & affect adversely the safety, therapeutic efficacy, appearance or elegance then they are said to be incompatible. ’’ DE F INITION

14. Types of Incompatibility Physical Chemical Therapeutic

15. Why to screen excipients? need to minimize no.of model formulations 2.provide rational basis for selecting excipients 3.Formulation stability studies are time consuming . Goal of the study ( Identify the excipients that) are co m pat i ble with A P I do not have impact on the stability of API Importance Stabity of formulation can be maximised. Helps to avoid surprise problems. 3.Essential for IND submission. 4.Bridges drug discovery and drug development

16. COM P A TIBILITY TESTS Aspects of compatibility tests are : Identification of compatible excipients for a formulation. Identification of stable storage conditions. Types : Solid state reactions : much slower and difficult to interpret. Liquid state reactions : easier to detect According to Stability Guidelines by FDA following conditions should be evaluated for solutions or suspensions Acidic or alkaline pH. Presence of added substances High oxygen and nitrogen atmospheres. Effect of stress testing conditions.

17. STEPS IN COMPATIBILITY STUDY There are four steps to consider. Sample preparation Statistical design Storage Method of analysis

18. SAMPLE PREPARATION FOR SOLID STATE REACTIONS: SampleA : - mixture of drug and excipient SampleB : - SampleA+ 5% moisture SampleC : - Drug itself without excipients All the sa m ples of dru g -exc i pient blen d s a r e ke p t for 1 -3 weeks at specified storage conditions. Then sample is physically observed . It is then assayed by TLC or HPLC or DSC . Whenever feasible, the degradation product are identified by MASS SPECTROSCOPY, NMR or other relevant analytical techniques. To determine Solid state stability profile of a new compound…. To test the Surface Oxidation…..

19. FOR LIQUID STATE REACTIONS: Place the drug in the solution of additives. Both flint and amber vials are used. This will provide information about -Susceptibility to oxidation. -Susceptibility to light exposure . -Susceptibility to heavy metals. In case of oral liquids, compatibility with ethanol, glycerin ,sucrose, preservatives and buffers are usually carried out.

20. Known Incompatibilities Functional group Incompatibility Type of reaction Primary amine Mono & Di-saccharides Amine-Aldehyde & Amine-Acetal Ester , Lactone Basic component Ester ba s e h y drol y si s , Ring opening, Aldehyde Amine, Carbohydrate Aldehyde-Amine, Schiff base Or Glycosylamine formation Carboxyl Base Salt formation Alcohol Oxygen Oxidation to Aldeh y de & Ketones Sulfhydryl Oxygen Dimerization Phenol Metal Complexation Gelatin- Capsule Shell Cationic Surfactant Denaturation

21. ANALYTICAL TECHNIQUES USED TO DETECT DRUS-EXCIPIENT COMPATIBILITY 1. Thermal methods of analysis   DSC- Differential Scanning Calorimetry D T A - Di f fe r enti a l The r m al A n a l ys i s Accelerated Stability Study FT-IR Spectroscopy DRS-Diffuse Reflectance Spectroscopy Chromatography SIC-Self Interactive Chromatography TLC-Thin Layer Chromatography HPLC-High Pressure Liquid Chromatography Miscellaneous Radiolabelled Techniques Vapour Pressure Osmometry Flourescence Spectroscopy

22. 1) DIFFRENTIAL THERMAL ANALYSIS Thermal Analysis is useful in the investigation of solid- state interactions. It is also useful in the detection of eutectics. Thermograms are generated for pure components and their physical mixtures with other components. In the absence of any interaction, the thermograms of mixtures show patterns corresponding to those of the individual components. In the event that interaction occurs, this is indicated in the thermogram of a mixture by the appearance of one or more new peaks or the disappearance of one or more peaks corresponding to those of the components.

23. 2) DSC- DIFFERENTIAL SCANNING CALORIMETRY DSC is widely used to investigate and predict any physico- chemical interaction between drug and excipients involving thermal changes.. METHOD -The preformulation screening of drug-excipient interaction requires (1 : 1)Drug:excipient ratio, to maximize the likehood of observing an interaction. -Mixture should be examined under N 2 to eliminate oxidative and pyrrolytic effects at heating rate ( 2, 5 or 10 c / min) on DSC apparatus.

24. LIMITATIONS OF DSC If thermal changes are very small, DSC can’t be used. DSC can not detect the incompatibilities which occur after long term storage. Eg. MCC / ASPIRIN… Not applicable if test material exhibits properties that make data interpretation difficult. A D V A N T AGE S : -Fast -Reliable and very less sample required.

25. 3) ACCELARETED STABILITY STUDY Different formulations of the same drug are prepared. Samples are kept at 40ºC / 75 % RH. Chemical stability is assessed by analyzing the drug content at regular interval. Amt. of drug degraded is calculated. % Drug decomposed VS time(month) is plotted.

26. 4) DIFFUSE REFLECTANCE SPECTROSCOPY Principle : “ Penetration of a portion of incident radiation flux into the interior of the solid sample, return of some portion of radiation to the surface of sample following partial absorption and multiple scattering at boundary of individual sample particles.” Detects the decomposed products, along with physical and chemical adsorption of excipients on to A.P.I. and vice versa. Example : Ethanol mediated interaction between dextroamphatamine sulphate and spray dried lactose in solid–solid mixture .

27. Diffuse reflectance spectroscopy is gaining increasing popularity among preformulation scientists as a tool to detect and monitor drug-excipient interactions. In this technique solid drugs, excipients, and their physical mixtures are exposed to incident radiation. A portion of the incident radiation is partly absorbed and partly reflected in a diffuse manner. The diffuse reflectance depends on the packing density of the solid, its particle size, and its crystal form, among other factors. When these factors are adequately controlled, diffuse reflectance spectroscopy can be used to investigate physical and chemical changes occurring on solid surfaces.

28. 5) SELF INTERACTIVE CHROMATOGRAPHY SIC is useful for proteinous drug and excipients. METHOD:- SIC is a modified type of affinity chromatography. Here, drug is made immobilized as the SP & soln. to be tested( excipient soln.) acts as MP. Measure Rt (Retention time) & compare with non –retained marker.

29. PRINCIPLE: - For different mobile phases (i.e. different excipients) the injected drug have different interactions (may be repulsive or attractive) with the SP of drug leads to shift in retention time ( Rt ) time FIGURE-1 FIGURE-2 FIGURE-3 When interaction When no net When attractive in t e r acti o n s ,it w i ll have longer retention time& wider peak is repulsive,a interaction between shar p er p eak is the immobilized obta i ne d at a drug,Rt=dead shor t er r e t enti o n v olume of c olumn.

30. 6) T L C AND HP T LC TLC is generally used as confirmative test of compatibility after performing DSC. S.P. consist of powder (Silica, Alumina, Polyamide, Cellulose & Ion exchange resin) adhered onto glass, plastic or metal plate. Solution of Drug, Excipient & Drug: Excipient mixture are prepared & spotted on the same baseline at the end of plate. The plate is then placed upright in a closed chamber containing the solvent which constitutes the M.P.

31. 7) RADIO LABELLED TECHNIQUES: It is i m portant w h en the A P I is having radi o – activ i t y . Method is carried out by using either 3H or 13C. Highly sensitive method but the cost of carrying out the method & the availability of well established other techniques & methods, this method is generally not preferred.

32. KINETICS OF STABILITY

33. ORDER OF REACTION: ZERO ORDER REACTION When the reaction rate is independent of concentration of the reacting substance, it depends on the zero power of the reactant and therefore is zero order reaction.

34. Rate of concentration decrease = - dCx = K……………………………(1) dt Integrating the equation yields X= Kt + constant…………………(2) The unit of K is conc time -1 , with typical units of mole L -1 s -1 . Half-life is given by equation t 1/2 = Co/2k .

35. GRAPH FOR ZERO ORDER time c o n c ent r ati o n Slope = k The value of K indicate the amount of drug that is degraded per unit time, and intercept of line at time zero is equal to constant in equation (2).

36. FIRST ORDER REACTION If concentration of reactant X is ‘a’ at beginning of reaction w hen t = 0, & i f amo u n t tha t has r e a c t ed a f t er ti m e t is denoted by x then amount of X remaining at time t will be (a-x). log (a-x) = log a – Kt/2.303 half-life of drug is calculated by equation t 1/2 = 0.693 k

37. GRAPH FOR FIRST ORDER time log (a-x) Slope = -k/2.303 If first order law is obeyed then a graph of log (a-x) vs time t will give straight line with slope of –K/2.303 and an intercept of log a at t = 0.

38. SECOND ORDER REACTION Rate of change in conc. of product and reactant is dependent on second power of conc. of single reactant or to first powers of the conc. of two reactants. Unit of second order reaction is conc .-1 time -1 and SI unit is Lmol -1 sec -1 . Half-life in this case is t 1/2 = 1/ak . The equation for this second order reaction is shown below Kt = 2.303 log b(a-x) , a ≠ b or (a-b) a(b-x) Kt = 1 - 1 , a = b a-x a

39. GRAPH FOR SECOND ORDER time log b(a-x)/a(b-x) Slope = (a-b)k/2.303

40. METHODS TO DETERMINE ORDER OF REACTION SUBSTITUTION METHOD DATA PLOTTING METHOD INITIAL RATE METHOD HALF-LIFE DETERMINATION METHOD SOFTWARE TOOLS FOR SECOND ORDER REACTIONS

41. STABILITY TESTING

42. STABILITY TESTING Stability : defined as capability of a particular formulation in a specific container/closure system to remain within its physical, chemical, microbiological, 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 OF STABILITY TESTING Provide evidence as to how the quality of drug product varies with time. Establish shelf life of drug product . Determines recommended storage conditions . Determine container closure system suitability.

43. IMPORTANCE OF STABILITY TESTING 1.Assurance to patient that drug is safe. 2.Legal requirement to provide data. 3.to protect the reputation of the manufacturer. 4.to provide a database . 5.to determine shelf life and storage conditions. 6.to verify that no changes have been introduced in the formulation or manufacturing process that can adversely affect the stability of the product .

44. TYPE OF STABILITY CHEMICAL • Each active ingredient retains its chemical integrity and labeled potency within specified limits. PHYSICAL:• Includes appearance, palatability, uniformity, dissolution and suspend ability are retained . MICROBIOLOGICAL:• Sterility or resistance to microbial growth is retained according to specific requirement . THERAPEUTIC:• Activity remains unchanged . TOXICOLOGIC:• No significant increase in toxicity.

45. STABILITY TESTING METHODS REAL TIME STABILITY TESTING ACCELERATED STABILITY TESTING RETAINED SAMPLE STABILITY TESTING CYCLIC TEMPERATURE STRESS TESTING

46. 1.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 appropriate frequency To distinguish instability from day to day Stability of reference material include the stability of reagent as well as consistency of performance 1.

47. 2.ACCELERATED STABILITY TESTING . A product is stressed at several high temp. & 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 to stress Refrigerated Assayed simultaneously

48. T he concept of accelerated stability testing is based upon the Arrhenius equation

49. 3. RETAINED SAMPLE STABILITY TESTING   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.

50. 4. 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 and specific chemical and physical degradation properties of the products. • the test should normally have 20 cycles.

51. SPECIFIC GUIDELINES UNDER Q1 Q1A (R2): Stability testing of new drug substances and products. Q1 B: Q1C: Q1 D: Q5 C : Photo-stability of new drug substances and products. Stability testing of new dosage forms. B r ac k eti n g & Ma trixi n g des i gn s f or s t abili t y t esti n g of new drug substances and products. Q1E: Evaluation of Stability data. Q1F Stability Data Package for Registration Applications in Climatic Zones III and IV. Stability testing of biotechnological/biological products.

52. TEST STORAGE CONDITION

53. Estimation of shelf life The time period during which a drug product is expected to remain within the approved shelf life specification, provided that it is stored under the conditions . The time period during which the drug maintain its 90% potency or loss not more than 10% potency. The shelf life is determined from the data obtained from the long term storage studies.

54. Expiration of date An expiration date is defined as the time up to which the product will remain stable when stored under recommended storage conditions . Thus , an expiration date is the date beyond which it is predicted that the product may no longer retain fitness for use . If the product is not stored in accordance with the manufacturer’s instructions, then the product may be expected to degrade more rapidly.

55. METHOD TO DETERMINE OVERAGES STEP I: - Perform the experiment and find out concentration of drug remaining at different time intervals at different temperature including room temperature. Plot the graph of concentration vs time for different temp. As shown in the figure measure the slope and from that get rate Constant K.

56. STEP :2 - Calculation for overages Plot the graph of time (Days) Vs conc. remaining. Extrapolate line from Y- axis, at 90% to the X- axis. The intersect point will give shelf life . To maintain or increase the shelf life as per need (from a to b as shown in fig.) draw a parallel line from Y to that of X, the intersect point at Y- axis will give the value of overages per 100 unit. As shown in the figure, The value of overages is 20%. So need to add 20 unit drug more to preexisting formulation

57. Most important guidelines are Food and Drug Administration (FDA) International Conference on Harmonization (ICH) European Union Guidelines (EU) Japanese Guidelines (MHW) Therapeutic Good Administration (TGA) – For Australia Gulf Central Committee (GCC) – For Gulf Countries Association of South East Asian Nations (ASEAN) Eastern Mediterranean Region etc.

58. ICH GUIDLINE What is ICH? The International Conference on Harmonization (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use is a unique project that brings together the regulatory authorities of Europe, Japan and the United States and experts from the pharmaceutical industry in the three regions to discuss scientific and technical aspects of product registration.

59. Objectives of ICH: Mo r e econo m ical us e o f human, an i mal , an d ma t er i al resources. Elim i n a tio n o f u n necessa ry d el a y i n t h e g lo b al development & availability of new medicines. Maintaining safeguards on Quality, safety & efficacy, and regulatory obligations to protect public health.

60. TOPICS OF ICH: Four Broad Categories - QSEM Quality (Q): Topics related to Manufacturing QA. Sa f e t y (S): T opics r el a t ed t o non - c li nical p h a r m a colo g y & toxicology studies. Efficacy (E): Topics related to Clinical studies in humans. Mu l ti d is c ip l i nar y ( M ): T opics a f f e c tin g mo r e tha n one discipline. Our concern is only with quality topics. QUALITY TOPICS: Consists of six subtopics:- Q1 : Stability testing Q2 : Analytical methods validation Q3 : Impurity testing Q4 : Pharmacopoeias Q5 : Quality of Biotechnological products Q6 : Specifications for new drug substances & products. Our concern is only Q1 (i.e. Stability testing).

61. 1) For Active S u b s t a nce : Stress Testing Selection of Batches Container Closure System Specification Testing Frequency Storage Conditions Stability Commitment Evaluation Statements/ Labelling

62. 2) For Pharmaceutical Product : Selection of Batches Container Closure System Specification Testing Frequency Storage Conditions Stability Commitment Evaluation Statements/ Labelling In-use stability Variations On-going Stability Studies

63. Stability Protocol and Report Batches tested General information Container/closure system Literature and supporting data Stability-indicating analytical methods Testing plan Test parameters Test results Other requirements (post-approval commitments) Conclusions

64. 1.PROCESSING FACTORS Particle size reduction (or milling) Wet granulation Compression Properties of polymeric film coatings Excipients Radiation ENVIRONMENTAL FACTORS Outside the dosage form Temperature Light Humidity 2.2 Inside the dosage form Oxidation M etal PH I o n i c st r ength General acid base catalysis/buffer Packaging components 6. F A C T O R O F S T A B I L ITY S T U D Y

65. Pharmaceutics- The science of Dosage Form Design by M. E. Aulton. (2 nd edition): pg.113 The Science & Practice of Pharmacy by Remington.(19 th edition): pg.1447 The Theory & Practice of Industrial Pharmacy by Leon Lachman, Herbet A. Lieberman, Joseph L. Kaing.(3 rd edition): pg.171 Pharmaceutical Dosage Forms by Leon Lachman, H. A. Lieberman; Vol.1: pg.1 Pharmaceutical Dosage Forms & Delivery Systems by H.C. Ansel, L.V.Allen P’ceutical preformulation &formulation, A practical guide by Mark gibson