Dissolution

Dissolution is mass transfer process.
Dissolution is mainly depend on aqueous solubility of drug.
It is process in which solid mass transfer in liquid medium.
Dissolution based on four process – 1. wetting 2. solubility 3. Swelling 4. diffusion.
Particle size, shape, surface area is important factor can affect the rate of dissolution of drug.
The aqueous solubility is increases, increases rate of dissolution drug

1. Dissolution Mr. S agar Kishor Savale [Department of Pharmacy (Pharmaceutics)] 2015-016 [email protected] 1 Monday, December 07, 2015

2. Content 1. Introduction 2. Important Terminology 3. Dissolution 4. Mechanism of dissolution 5. Why dissolution studies 6. Importance and application 7. Application of in vitro dissolution studies 8. General application of dissolution 9. Theory's of dissolution 10. Intrinsic dissolution rate Monday, December 07, 2015 2

3. Content 11. Factor affecting on dissolution 12. Methods of dissolution 13. In vivo dissolution studies 14. Dissolution pattern 15. In vitro study is more accepted as compared to In vivo study 16. IV – IVC 17. Biopharmaceutical classification system (BCS) 18. Biowaiver 19. Dosage from conducted dissolution study 20. Reference Monday, December 07, 2015 3

4. 1. Introduction Dissolution is mass transfer process. Dissolution is mainly depend on aqueous solubility of drug. It is process in which solid mass transfer in liquid medium . Dissolution based on four process – 1. wetting 2. solubility 3. Swelling 4. diffusion. Particle size, shape, surface area is important factor can affect the rate of dissolution of drug. The aqueous solubility is increases , increases rate of dissolution drug Monday, December 07, 2015 4

5. 2. Important Terminology Dissolution - solid mass transfer process in to liquid medium. Diffusion - diffusion is mass transfer process of individual molecules of atoms having continuous random molecular motion contain in concentration gradient is known has Diffusion. Dialysis - separation of easily diffusible particle from poorly diffusible particle through semipermeable Membrane. Ultrafiltration - separation of colloidal particle from sub colloidal particle through semipermeable membrane. Monday, December 07, 2015 5

6. Monday, December 07, 2015 6 Osmosis - The passage of solvent molecule into solution through semipermeable membrane. Semipermeable membrane – Thin layer that can separate two phases. Steady sate - Mass transfer process is remains constant per unit time. Non steady state - Mass transfer process is not remains constant per unit time. Osmotic pressure - The pressure is exerted in walles of semipermeable membrane through concentration gradient. Diffusant(penetrant ) - the amount of material transport in semipermeable membrane. Con. Gradient - concentration of material transport in region of high con. To region of low con.

7. Monday, December 07, 2015 7 R.D.S. ( rate determining step)- event occurs in longer period of time. Hydrophilic drug – r.d.s . absorption Lipophilic drug – r.d.s . dissolution Dosage system- 1 ) conventional 2) sustained & Controlled release system (Not undergoes disintegration )

8. 3. Dissolution Definition - Dissolution is a process in which a solid substance solubilizes in a given solvent i.e. mass transfer from the solid surface to the liquid phase . Rate of dissolution - is the amount of drug substance that goes in solution per unit time under standardized conditions of liquid/solid interface, temperature and solvent composition. Monday, December 07, 2015 8

9. 4. Mechanism of Dissolution Dissolution is a mass transfer process Sink condition – The concentration of receptor compartment is maintain lower level as compared to Donor compartment is known as sink condition. Non sink condition – The concentration of receptor compartment is not maintain at lower level as compared to donor compartment. Monday, December 07, 2015 9

10. 5. Why dissolution studies? To show that the release of drug from the tablet is close to 100%. To show that the rate of drug release is uniform batch to batch. And to show that release is equivalent to those batches proven to be bioavailable and clinically effective. Monday, December 07, 2015 10

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15. 6. Importance And Applications Results from in-vitro dissolution rate experiments can be used to explain the observed differences in in-vivo availability. (in vivo and in vivo dissolution test) Dissolution testing provides the means to evaluate critical parameters such as adequate bioavailability and provides information necessary to formulator in development of more efficacious and therapeutically optimal dosage forms. most sensitive and reliable predictors of in-vivo availability . Dissolution analysis of pharmaceutical dosage forms has emerged as single most important test that will ensure quality of product. (qualitative and quantitative analysis) It can ensure bioavailability of product between batches that meet dissolution criteria. Ensure batch-to-batch quality equivalence both in-vitro and in-vivo , but also to screen formulations during product development to arrive at optimally effective products. Physicochemical properties of model can be understood needed to mimic in-vivo environment. Such models can be used to screen potential drug and their associated formulations for dissolution and absorption characteristics. Monday, December 07, 2015 15

16. 7. Application of In vitro dissolution studies 1. Product Development Important tool during development of dosage form. Aids in guiding the selection of prototype formulations and for determining optimum levels of ingredients to achieve drug release profiles, particularly for extended release formulations. Also guides in selection of a “market-image” product to be used in pivotal in-vivo bioavailability or bioequivalence studies. 2. Quality Assurance D.T. performed on future production lots and is used to assess the lot-to-lot performance characteristics of drug product and provide continued assurance of product integrity/similarity. 3. Product Stability In-vitro dissolution also used to assess drug product quality with respect to stability and shelf-life. As product age, physicochemical changes to the dosage form may alter dissolution characteristics of drug product over time. For some products, polymorph transformations to more stable, and hence less soluble crystalline forms may result in reduced dissolution rates. Monday, December 07, 2015 16

17. Monday, December 07, 2015 17 4. Comparability Assessment Also useful for assessing the impact of pre- or post- approval changes to drug product such as changes to formulation or manufacturing process. Thus, in-vitro comparability assessment is critical to ensure continued performance equivalency and product similarity. 5. Waivers Of In-vivo Bioequivalence Requirements In-vitro dissolution testing or drug release testing may be used for seeking waiver of required product to conduct in-vivo bioavailability or bioequivalence studies. 8. General Applications of Dissolution 1) Product development 2) Quality assurance 3) Product stability 4) Comparability assessment

18. 9. Theories of Drug Dissolution Diffusion layer model/Film Theory Danckwert’s model/Penetration or surface renewal Theory Interfacial barrier model/Double barrier or Limited solvation theory. Monday, December 07, 2015 18

19. 9.1 Diffusion layer model/Film Theory It involves two steps Solution of the solid to form stagnant film or diffusive layer which is saturated with the drug Diffusion of the soluble solute from the stagnant layer to the bulk of the solution; this is r.d.s in drug dissolution. Monday, December 07, 2015 19

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22. Monday, December 07, 2015 22 The rate of dissolution is given by Noyes and Whitney Where , dc/dt= dissolution rate of the drug K= dissolution rate constant C s = concentration of drug in stagnant layer C b = concentration of drug in the bulk of the solution at time t

23. Monday, December 07, 2015 23 Modified Noyes-Whitney’s Equation

24. Monday, December 07, 2015 24 This is first order dissolution rate process, for which the driving force is concentration gradient. This is true for in-vitro dissolution which is characterized by non-sink conditions. The in-vivo dissolution is rapid as sink conditions are maintained by absorption of drug in systemic circulation i.e. C b =0 and rate of dissolution is maximum.

25. Monday, December 07, 2015 25 Under sink conditions, if the volume and surface area of the solid are kept constant, then dC = K dt This represents that the dissolution rate is constant under sink conditions and follows zero order kinetics.

26. Monday, December 07, 2015 26 Dissolution rate under non-sink and sink conditions

27. Monday, December 07, 2015 27 Hixon-Crowell’s cubic root law of dissolution takes into account the particle size decrease and change in surface area, W 1/3 – W 1/3 = K t Where, W =original mass of the drug W=mass of drug remaining to dissolve at time t K t =dissolution rate constant.

28. 9.2 Danckwert’s model/Penetration or surface renewal Theory Dankwert takes into account the eddies or packets that are present in the agitated fluid which reach the solid-liquid interface, absorb the solute by diffusion and carry it into the bulk of solution. These packets get continuously replaced by new ones and expose to new solid surface each time, thus the theory is called as surface renewal theory. Monday, December 07, 2015 28

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31. Monday, December 07, 2015 31 The Danckwert’s model is expressed by equation

32. Monday, December 07, 2015 32 9.3 Interfacial barrier model/Double barrier or Limited solvation theory The Diffusion layer model and the Dankwert’s model were based on two assumptions: 1) The rate determining step that controls dissolution is the mass transport. 2) Solid solution equilibrium is achieved at the solid/liquid interface.  According to interfacial barrier model, an intermediate conc. can exist at the interface as a result of solvation mechanism and is a function of solubility rather than diffusion.  When considering the dissolution of the crystal will have a different interfacial barrier given by following equation,

33. Monday, December 07, 2015 33 G = ki (Cs – Cb) Where , G = dissolution per unit area Ki = effective interfacial transport constant In this theory, the diffusivity D may not be independent of saturation conc. Cs . The interfacial barrier model can be extended to both Diffusion layer model and the Dankwert’s model.

34. 10. Intrinsic Dissolution rate Rate which is independent of rate of agitation, area of solute available, etc. Intrinsic Dissolution Rate (IDR): rate of mass transfer per area of dissolving surface. It is independent of boundary layer thickness and volume of slolvent . Monday, December 07, 2015 34

35. Monday, December 07, 2015 35 Thus, IDR = k 1 C s IDR measures the intrinsic properties of the drug only as a function of the dissolution medium, e.g. its pH, ionic strength, counter ions, etc.)

36. 11. Factor affecting dissolution rate Physicochemical Properties of Drug Drug Product Formulation Factors Processing Factors Factors Relating Dissolution Apparatus Factors Relating Dissolution Test Parameters Monday, December 07, 2015 36

37. 1. Physicochemical Properties of Drug 1) Drug Solubility Solubility of drug plays a prime role in controlling its dissolution from dosage form. Aqueous solubility of drug is a major factor that determines its dissolution rate. Minimum aqueous solubility of 1% is required to avoid potential solubility limited absorption problems. Studies of 45 compound of different chemical classes and a wide range of solubility revealed that initial dissolution rate of these substances is directly proportional to their respective solubility. Fig shows a log-log plot of solubility of several drug Vs their corresponding intrinsic rates of dissolution at infinite rotation speed. Evident from graph that compounds with high solubility exhibit significantly higher dissolution rates. Monday, December 07, 2015 37

38. Monday, December 07, 2015 38 2) Salt Formation It is one of the common approaches used to increase drug solubility and dissolution rate. It has always been assumed that sodium salts dissolve faster than their corresponding insoluble acids. Eg. sodium and potassium salts of Peniciilin G, sulfa drugs, phenytoin, barbiturates etc. While in case of Phenobarbital dissolution of sodium salt was slower than that of weak acid. Same is the case for weak base drug, strong acid salts, such as hydrochlorides and sulphates of weak bases such as epinephrine, tetracycline are commonly used due to high solubility. However, free bases of chlortetracycline, methacycline were more soluble than corresponding hydrochloride salt at gastric pH values, due to common ion suppression.

39. Monday, December 07, 2015 39 3) Particle Size There is a direct relationship between surface area of drug and its dissolution rate. Since, surface area increases with decrease in particle size, higher dissolution rates may be achieved through reduction of particle size. Micronization of sparingly soluble drug to reduce particle size is by no means a guarantee of better dissolution and bioavailability. Micronization of hydrophobic powders can lead to aggregation and floatation when powder is dispersed into dissolution medium. So, mere increase in S.A. of drug does not always guarantee an equivalent increase in dissolution rate. Rather, it is increase in the “effective” S.A., or area exposed to dissolution medium and not the absolute S.A. that is directly proportional to dissolution rate. Hydrophobic drugs like phenacetin, aspirin shows decrease in dissolution rate as they tend to adsorb air at the surface and inhibit their wettability. Problem eliminated by evacuating surface from adsorbed air or by use of surfactants. So these drugs in-vivo exhibit excellent wetting due to presence of natural surfactants such as bile salts.

40. Monday, December 07, 2015 40 4) Solid State Characteristics Solid phase characteristics of drug, such as amorphicity, crystallinity, state of hydration and polymorphic structures have significant influence on dissolution rate. Anhydrous forms dissolve faster than hydrated form bcz they are thermodynamically more active than hydrates. Eg. Ampicillin anhydrate faster dissolution rate than trihydrate. Amorphous forms of drug tend to dissolve faster than crystalline materials. E.g. Novobiocin suspension, Griseofulvin. Where in the dissolution rate of amorphous erythromycin estolate is markedly lower than the crystalline form of erythromycin estolate. Metastable (high activation energy) polymorphic forms have better dissolution than stable forms.

41. Monday, December 07, 2015 41 5) Co-precipitation Dissolution rate of sulfathiazole could be significantly increased by co-precipitating the drug with povidone.

42. 2. Drug Product Formulation Factors Dissolution rate of pure drug can be altered significantly when mixed with various adjuncts during manufacturing process such as diluents, dyes, binders, granulating agents, disintegrants and lubricants. Generically identical tablet or capsules exhibited differences in their dissolution rates of their active ingredients. 1 ) Diluents Diluents in capsule & tablet influence the dissolution rate of drug. Studies of starch on dissolution rate of salicylic acid tablet by dry double compression process shows three times increase in dissolution rate when the starch content increase from the 5 – 20 %. Here starch particles form a layer on the outer surface of hydrophobic drug particles resulting in imparting hydrophilic character to granules & thus increase in effective surface area & rate of dissolution. Monday, December 07, 2015 42 Different types of dissolution apparatus utilized affect ranking of different varieties of starch. With stirring type of agitation, order was potato starch>cornstarch>arrowroot starch>rice starch. With oscillating type, a different order observed. Corn>rice>arrowroot>potato. The dissolution rate is not only affected by nature of the diluent but also affected by excipient dilution ( drug/excipient ratio). E.g . in quinazoline comp. dissolution rate increases as the excipient /drug ratio increases from 3:1 to 7:1 to 11:1.

43. Monday, December 07, 2015 43 2 ) Disintegrants Disintegrating agent added before & after the granulation affects the dissolution rate. Studies of various disintegrating agents on Phenobarbital tablet showed that when copagel (low viscosity grade of Na CMC) added before granulation decreased dissolution rate but if added after did not had any effect on dissolution rate. Microcrystalline cellulose is a very good disintegrating agent but at high compression force, it may retard drug dissolution. Starch is not only an excellent diluent but also superior disintegrant due to its hydrophilicity and swelling property. Disintegration and dissolution rate of disintegrants with moderate swelling capacity depend to a large extent on mixing time of drug/excipient preblende. With lubricant. On other hand, disintegrants with strong swelling capacity such as sodium starch glycolate were hardly affected by mixing time with lubricant.

44. Monday, December 07, 2015 44 3) Binders And Granulating Agents The hydrophilic binder increase dissolution rate of poorly wettable drug. Large amt. of binder increase hardness & decrease disintegration /dissolution rate of tablet. Non aqueous binders such as ethyl cellulose also retard the drug dissolution. Phenobarbital tablet granulated with gelatin solution provide a faster dissolution rate in human gastric juice than those prepared using Na – carboxymethyl cellulose or polyethylene glycol 6000 as binder . Gelatin imparted hydrophilic character to hydrophobic drug surface whereas PEG 6000 formed a poorly soluble complex while NA-CMC was converted to its less soluble acid form at the low pH of gastric fluid. In Phenobarbital tablet, faster dissolution rate was observed with 10% gelatin whereas decrease in dissolution rate with 20% gelatin. This was due to higher concentration which formed a thick film around tablet. Water soluble granulating agent Plasdone gives faster dissolution rate compared to gelatin.

45. Monday, December 07, 2015 45 4) Lubricants Lubricants are hydrophobic in nature (metallic stearates) and prolong tablet disintegration time by forming water repellant coat around individual granules. This retarding effect is most imp factor in influencing rate of dissolution of solid dosage forms. Both amount and method of addition affect the property. It should be added in small amount (1% or less) and should be tumbled or mixed gently for only very short time. Prolonged mixing the dissolution time. However , if an enhancing effect in dissolution of hydrophobic granules is desired, water soluble lubricant such as SLS or CARBOWAXES may be used.

46. Monday, December 07, 2015 46 5) Surfactants They enhance the dissolution rate of poorly soluble drug. This is due to lowering of interfacial tension, increasing effective surface area, which in turn results in faster dissolution rate. E.g Non-ionic surfactant Polysorbate 80 increase dissolution rate of phenacetin granules. The increase was more pronounced when the surfactant was sprayed on granules than when it was dissolved in granulating agent. 6) Water-soluble Dyes Dissolution rate of single crystal of sulphathiazole was found to decrease significantly in presence of FD&C Blue No.1. The inhibiting effect was related to preferential adsorption of dye molecules on primary dissolution sources of crystal surfaces. They inhibit the micellar solubilization effect of bile salts on drug. Cationic dyes are more reactive in lower conc. than are anionic dyes. 7) Coating Polymers Tablets with MC coating were found to exhibit lower dissoln profiles than those coated with HPMC at 37ºC. The differences are attributed to thermal gelation of MC at temp near 37º, which creates a barrier to dissoln process & essentially changes the dissoln medium. This mechanism is substantiated by the fact that at temp below the gel point & at increased agitation, the effect disappears.

47. 3. Processing Factors 1) Method Of Granulation Granulation process in general enhances dissolution rate of poorly soluble drug. Wet granulation is traditionally considered superior. But exception is the dissolution profile of sodium salicylate tablets prepared by both wet granulation and direct compression where the dissolution was found more complete and rapid in latter case. A newer technology called as APOC “Agglomerative Phase of Comminution” was found to produce mechanically stronger tablets with higher dissolution rates than those made by wet granulation. A possible mechanism is increased internal surface area of granules produced by APOC method. Monday, December 07, 2015 47

48. Monday, December 07, 2015 48 2) Compression Force The compression process influence density, porosity, hardness, disintegration time & dissolution of tablet. First condition, higher compression force increase the density & hardness of tablet, decrease porosity & hence penetrability of solvent into the tablet retard the wettability by forming a firmer & more effective sealing layer by the lubricant and in many case tighter bonding between the particle so decrease dissolution rate of tablet . Second condition, higher compression force cause deformation, crushing or fracture of drug particles into smaller ones or convert spherical granules into disc shaped particles with a large increase in the effective surface area so increase in dissolution rate. First cond. Second cond. Combination of both conditions can occur In short dissolution decrease at lower pressure (better bonding), then increase at higher pressure (crushing effect) and decrease again with further increase in pressure bcz of extra rebonding and formation of denser tablets with poorer dissolution characteristics.

49. Monday, December 07, 2015 49 3) Drug Excipient Interaction These interactions occur during any unit operation such as mixing, milling, blending, drying, and/or granulating result change in dissolution. The dissolution of prednisolone found to depend on the length of mixing time with Mg-stearate Similar as increase in mixing time of formulation containing 97 to 99% microcrystalline cellulose or another slightly swelling disintegrant result in enhance dissolution rate. Polysorbate-80 used as excipient in capsules causes formation of formaldehyde by autoxidation which causes film formation by denaturing the inner surface of capsule. This causes decrease in dissoln rate of capsules.

50. Monday, December 07, 2015 50 4) Storage Conditions Dissolution rate of Hydrochlorthiazide tablets granulated with acacia exhibited decrease in dissolution rate during 1 yr of aging at R.T. A similar decrease was observed in tablets stored for 14 days at 50-80ºC or for 4 weeks at 37ºC. For tablets granulated with PVP there was no change at elevated temperature but slight decrease at R.T. Tablets with starch gave no change in dissoln. rate either at R.T. or at elevated temperature.

51. 4. Factors Relating Dissolution Apparatus 1) Agitation Relationship between intensity of agitation and rate of dissolution varies considerably acc. to type of agitation used, the degree of laminar and turbulent flow in system, the shape and design of stirrer and physicochemical properties of solid. Speed of agitation generates a flow that continuously changes the liq/solid interface between solvent and drug. In order to prevent turbulence and sustain a reproducible laminar flow, which is essential for obtaining reliable results, agitation should be maintained at a relatively low rate. Thus , in general relatively low agitation should be applied. Basket Method- 100 Rpm Paddle Method- 50-75 rpm Monday, December 07, 2015 51

52. Monday, December 07, 2015 52 2) Stirring Element Alignment The USP / NF XV states that the axis of the stirring element must not deviate more than 0.2 mm from the axis of the dissolution vessel which defines centering of stirring shaft to within ±2 mm. Studies indicant that significant increase in dissolution rate up to 13% occurs if shaft is offset 2-6 mm from the center axis of the flask. Tilt in excess of 1.5 0 may increase dissolution rate from 2 to 25%. 3 ) Sampling Probe Position & Filter Sampling probe can affect the hydrodynamic of the system & so that change in dissolution rate. For position of sampling, USP / NF states that sample should be removed at approximately half the distance from the basket or paddle to the dissolution medium and not closer than 1 cm to the side of the flask. Filter material must be saturated with the drug by repeated passage to avoid losses that might go undetected during the test sampling. Accumulation of the particulate matter on the surface may cause significant error in the dissolution testing.

53. 5. Factors Relating Dissolution Test Medium 1 ) Temperature Drug solubility is temperature dependent, therefore careful temperature control during dissolution process is extremely important. Generally , a temp of 37º ± 0.5 is maintained during dissolution determination of oral dosage forms and suppositories. However, for topical preparations temp as low as 32º and 25º have been used 2 ) Dissolution Medium It is very imp factor affecting dissolution and is itself affected by number of factors such as: A . Effect of pH Weak acids, dissoln. rate increases with increase in pH whereas for weak bases, increase with decrease in pH. Monday, December 07, 2015 53

54. Monday, December 07, 2015 54 B . Volume of dissolution medium and sink conditions Volume generally 500, 900 or 1,000 ml. Simulated gastric fluid(SGF) - pH 1.2. Simulated intestinal fluid (SIF)- pH 6.8 (not exceed pH 8.0). The need for enzymes should be evaluated case-by-case like…. (Pepsin with SGF and pancreatin with SIF If drug is poorly soluble, a relatively large amount of fluid should be used if complete dissolution is to be expected. In order to minimize the effect of conc. gradient and maintain sink conditions, the conc. of drug should not exceed 10-15% of its max. Solubility in dissoln. medium selected. For most of the drugs about 1 L is more than sufficient to maintain sink conditions. However, some insoluble drug present a problem as to handling of huge volume of dissoln. medium that would be required to maintain the sink conditions. For these, different approaches have been tried like…. Continous flow method where fresh solvent is pumped continuously into dissoln flask at a fixed flow rate while maintaining a constant volume. (approach 1) Use of non-ionic surfactant in conc. above CMC. (approach 2) Use of alcoholic solution (10-30%). (approach 3)

55. Monday, December 07, 2015 55 C. Deaeration of dissolution medium Dissolved air in distilled water could significantly lower its pH and consequently affect the dissolution rate of drugs that are sensitive to pH changes, weak acids. Another effect is to be released from the medium in form of tiny air bubbles. These bubbles collect at the surface of the dosage forms, thereby acting as a hydrophobic barrier between solvent and solid surface. This inhibits wetting and reduction of S.A. and lower dissoln. rate.

56. Monday, December 07, 2015 56 Dissolution Medium Example Water Ampicillin caps., butabarbital sodium tabs. Buffers Azithromycin caps., paracetamol tabs. HCL solution Cemetidine tabs. Simulated gastric fluid Astemizole tabs., piroxicam caps. Simulated intestinal fluid Valproic caps., Glipizide tabs. Surfactant solution Clofibrate caps, danazol caps

57. 12. Methods of Dissolution 12.1 Official Methods 12.2 Non-official methods 12.1 Official Method 1. Beaker method 2. closed method 3. Dialysis method Monday, December 07, 2015 57

58. 1. Beaker method In this type of method can contain in all IP and USP dissolution apparatus. Mechanism - Non sink condition. 12.1.1 IP apparatus – First is Paddle apparatus (IP) Second is Basket apparatus (IP) [(IP – Indian Pharmacopeia) , ( USP – United state Pharmacopeia)] Monday, December 07, 2015 58

59. USP apparatus Apparatus Classification in USP Apparatus 1 (rotating basket) Apparatus 2 (paddle assembly) Apparatus 3 (reciprocating cylinder) Apparatus 4 (flow-through cell) Apparatus 5 (paddle over disk) Apparatus 6 (cylinder) Apparatus 7 (reciprocating holder) Monday, December 07, 2015 59

60. Monday, December 07, 2015 60 Apparatus   Name Drug Product Apparatus 1 Rotating basket Tablets Apparatus 2 Paddle Tablets, capsules, modified drug products, suspensions Apparatus 3 Reciprocating cylinder Extended-release drug products Apparatus 4 Flow cell Drug products containing low-water-soluble drugs Apparatus 5 Paddle over disk Transdermal drug products Apparatus 6 Cylinder Transdermal drug products Apparatus 7 Reciprocating disk Transdermal drug products Rotating bottle (Non-USP-NF) Extended-release drug products (beads) Diffusion cell (Franz) (Non-USP-NF) Ointments, creams, transdermal drug products

61. Monday, December 07, 2015 61 Type of dosage form Recommended Apparatus Solid oral dosage forms Basket , paddle, reciprocating, cylinder, or flow-through cell (conventional) Basket and paddle Oral suspensions Paddle , Spin filter Oral disintegrating tablets Paddle Chewable tablets Basket, paddle, or reciprocating, cylinder with glass beads Transdermal - patches Paddle over disk Topical - semisolids Franz cell diffusion system Suppositories Paddle, modified basket, or dual, chamber flow-through cell Chewing gum Special apparatus [European Pharmacopoeia (PhEur)] Powders and granules Flow-through cell (powder/granule sample cell) Micro particulate formulations Modified flow-through cell Implants Modified flow-through cell

62. Monday, December 07, 2015 62 USP App DESCRIPTION ROT. Speed dosage Form I BASKET 50-120 rpm IR , DR, ER II PADDLE 25-50 rpm IR , DR, ER III RECIPROCATING CYLINDER 6-35 dpm IR , ER IV FLOW-THRU CELL N/A ER , POORLY SOLUBLE API V PADDLE OVER DISK 25-50 rpm TRANSDERMAL VI CYLINDER N/A TRANSDERMAL VII RECIPROCATING HOLDER 30 rpm ER

63. Condition (for all general) 1. Temp. - 37±0.5˚C 2. PH - ±0.05 unit in specified monograph 3. Capacity – 1000 ml 4. Distance between inside bottom of vessel and paddle/basket is maintained at 25±2 mm. 5. For enteric coated dosage form it is first dissolved in 0.1 N HCl & then in buffer of pH 6.8 to measure drug release. (Limit – NMT 10% of drug should dissolve in the acid after 2hr.and about 75% of it should dissolve in the buffer after 45 min. Monday, December 07, 2015 63

64. 1. USP Apparatus 1 It is a Basket type of apparatus . It is used for highly water soluble drugs E.g . lithium acetate tablet (USP) Phenytoin Sodium (USP) Parts of Basket type apparatus Cylindrical vessel Water bath Variable speed Motor Basket Sample Withdrawal point (Sample Removing Point) Monday, December 07, 2015 64

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67. Monday, December 07, 2015 67 Cylindrical Vessel – It is made by glass and other transporting material having bottom flask and cylindrical in shape having capacity 900 ml or 1000 ml (1 lit.) Water bath – It is important to maintain the temperature at 37±0.5˚C Variable speed motor - The rotating shaft attached to the variable speed motor having RPM 25 to 100 rpm . Basket – It is made b y stain less still 316 and mesh size is 10, 20, 22, 40, but mesh size 20 is more accepted. It is important to determine the rate of dissolution of drug. Sample Withdrawal point (Sample Removing Point ) – The point is important to remove sample from dissolution vessel from dissolution media.

68. Monday, December 07, 2015 68 Useful for : Capsules, Beads , Delayed release / Enteric Coated dosage forms , Floating dosage forms Standard volume : 900/1000 ml 1 , 2, 4 liter vessels Advantages : 1) more than 200 monographs. 2 ) Full pH change during the test 3) Can be easily automated which is important for routine investigation. Disadvantages : 1 ) Disintegration-dissolution interaction 2) Hydrodynamic Dead jone under the basket. 3) Degassing is particularly important 4) Limited volume-----sink condition for poorly soluble drugs . 40 mesh basket 20 mesh basket 10 mesh basket suppository basket

69. 2. USP Apparatus 2 It is paddle type of apparatus It is used for less water soluble drugs. Example – 1. danapzole capsule USP Parts Cylindrical vessel Water bath Variable speed Motor paddle Sample Withdrawal point (Sample Removing Point) Monday, December 07, 2015 69

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73. Monday, December 07, 2015 73 PTFE coated paddle Solid PTFE coated paddle

74. Monday, December 07, 2015 74 Cylindrical Vessel – It is made by glass and other transporting material having bottom flask and cylindrical in shape having capacity 900 ml or 1000 ml (1 lit.) Water bath – It is important to maintain the temperature at 37±0.5˚C Variable speed motor - The rotating shaft attached to the variable speed motor having RPM 25 to 100 rpm . Paddle – It is made b y stain less still 316 and it is used as paddle bleades and shaft ; It is important to determine the rate of dissolution of drug. Sample Withdrawal point (Sample Removing Point) – The point is important to remove sample from dissolution vessel from dissolution media .

75. Monday, December 07, 2015 75 Useful for : Tablets, Capsules, Beads, Delayed release, enteric coated dosage forms Standard volume: 900/1000 ml Advantages 1. Easy to use 2. Robust 3. Can be easily adapted to apparatus 5 4. long experience 5. pH change possible 6. Can be easily automated which is important for routine investigations. Disadvantages 1. pH/media change is often difficult 2. Hydrodynamics are complex, they vary with site of the dosage form in the vessel (sticking, floating) and therefore may significantly affect drug dissolution 3. Coning.

76. Monday, December 07, 2015 76 Sinkers for floating dosage forms

77. Monday, December 07, 2015 77 Limitations of USP Apparatus 1 and 2 1. USP2 (and USP1) Apparatus has plenty of HYDRODYNAMICS. 2. Complicated 3-dimensional flow generated by the paddle. 3. Significant impact of convective transport –Conditions used (50 – 100 rpm) highly exaggerates flow in the GI. 4. If Static-tank model used – sink conditions artificially generated to simulate sink in GI. 5. Use of solvents and surfactants non-native to GI.

78. 3. Apparatus 3 It is a Reciprocating cylindrical apparatus . This method adopts the USP disintegration “basket and rack” assembly for the dissolution test. The disks are not used. This method is less suitable for precise dissolution testing due to the amount of agitation and vibration involved. E.g. Chlorpheniramine ER tablets, Carbamazepine chewable tablet Monday, December 07, 2015 78

79. Monday, December 07, 2015 79 The assembly consists of a set of cylindrical, flat-bottomed glass vessels; a set of glass reciprocating cylinders; stainless steel fittings (type 316 or equivalent) and screens that are made of suitable nonsorbing and nonreactive material(polypropelene) and that are designed to fit the tops and bottoms of the reciprocating cylinders; and a motor and drive assembly to reciprocate the cylinders vertically inside the vessels. The vessels are partially immersed in a suitable water bath of any convenient size that permits holding the temperature at 37 ± 0.5 during the test. The dosage unit is placed in reciprocating cylinder & the cylinder is allowed to move in upward and downward direction constantly. Release of drug into solvent within the cylinder measured. Useful for: Tablets , Beads , controlled release formulations Standard volume: 200-250 ml/station Advantages : 1) Easy to change the pH-profiles 2) Hydrodynamics can be directly influenced by varying the dip rate . Disadvantages: 1) small volume (max. 250 ml) 2) Little experience 3 ) Limited data

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81. 4. Apparatus IV Open Flow through cell The assembly consists of a reservoir and a pump for the Dissolution Medium; a flow-through cell; a water bath that maintains the Dissolution Medium at 37 ± 0.5 The cell size is specified in the individual monograph. The pump forces the Dissolution Medium upwards through the flow-through cell. Place the glass beads into the cell specified in the monograph. Place 1 dosage unit on top of the beads or, if specified in the monograph, on a wire carrier. Assemble the filter head, and fix the parts together by means of a suitable clamping device. Introduce by the pump the Dissolution Medium warmed to 37 ± 0.5 through the bottom of the cell to obtain the flow rate specified in the individual monograph. Collect the elute by fractions at each of the times stated. Perform the analysis as directed in the individual monograph. Monday, December 07, 2015 81

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85. Monday, December 07, 2015 85 Useful for: Low solubility drugs , Micro particulates, Implants , Suppositories , Controlled release formulations Variations: (A) Open system & (B) Closed system . Advantages 1. Easy to change media pH 2. PH-profile possible 3. Sink conditions Disadvantages 1. Deaeration necessary 2. High volumes of media 3. Labor intensive

86. 5. Apparatus 5 Modification of Apparatus 2 . (Paddle over disk apparatus) Here, stainless steel disk designed for holding transdermal system at the bottom of the vessel. The disk/device should not sorb, react with, or interfere with the specimen being tested. The disk holds the system flat and is positioned such that the release surface is parallel with the bottom of the paddle blade. Monday, December 07, 2015 86

87. Monday, December 07, 2015 87 Use the paddle and vessel assembly from Apparatus 2 with the addition of a stainless steel disk assembly designed for holding the transdermal system at the bottom of the vessel. Other appropriate devices may be used, provided they do not sorb, react with, or interfere with the specimen being tested The disk assembly for holding the transdermal system is designed to minimize any “dead” volume between the disk assembly and the bottom of the vessel. The disk assembly holds the system flat and is positioned such that the release surface is parallel with the bottom of the paddle blade The vessel may be covered during the test to minimize evaporation. Useful for : Transdermal patches Standard volume : 900 ml Disadvantages : Disk assemmbly restricts the patch size. Borosilicate Glass 17 mesh is standard (others available) Accommodates patches of up to 90mm

88. Monday, December 07, 2015 88 US 724 APPARATUS Transdermal Patch Retainer (Hanson Style)

89. Monday, December 07, 2015 89

90. Monday, December 07, 2015 90

91. 6. Apparatus 6 It is Cylindrical apparatus Same as apparatus 1,except to replace the basket and shaft with a S.S. cylinder stirring element. Temperature - 32 ± 0.5° The dosage unit is placed on the cylinder. Distance between the inside bottom of the vessel and cylinder is maintained at 25 ± 2 mm. Monday, December 07, 2015 91

92. Monday, December 07, 2015 92

93. 7. Apparatus 7 Reciprocating disk / Holder he assembly consists of a set of calibrated solution containers, a motor and drive assembly to reciprocate the system vertically . Various type of sample holder are used. Monday, December 07, 2015 93

94. Monday, December 07, 2015 94 The assembly consists of a set of volumetrically calibrated solution containers made of glass or other suitable inert material , a motor and drive assembly to reciprocate the system vertically and a set of suitable sample holders. The solution containers are partially immersed in a suitable water bath of any convenient size that permits maintaining the temperature, inside the containers at 32 ± 0.5 For Coated tablet drug delivery system attach each system to be tested to a suitable sample holder (e.g., by gluing system edge with 2-cyano acrylate glue onto the end of a plastic rod or by placing the system into a small nylon net bag at the end of a plastic rod or within a metal coil attached to a metal rod). For Transdermal drug delivery system attach the system to a suitable sized sample holder with a suitable O-ring such that the back of the system is adjacent to and centered on the bottom of the disk-shaped sample holder or centered around the circumference of the cylindrical-shaped sample holder. Trim the excess substrate with a sharp blade. For Other drug delivery systems attach each system to be tested to a suitable holder as described in the individual monograph.

95. Monday, December 07, 2015 95 Suspend each sample holder from a vertically reciprocating shaker such that each system is continuously immersed in an accurately measured volume of Dissolution Medium within a calibrated container.  Reciprocate at a frequency of about 30 cycles per minute with amplitude of about 2 cm, or as specified in the individual monograph, for the specified time in the medium specified for each time point.  Perform the analysis as directed in the individual monograph.

96. Monday, December 07, 2015 96 8. Simple view of all dissolution apparatus

97. 2. Open Flow-through Compartment System The dosage form is contained in a small vertical glass column with built in filter through which a continuous flow of the dissolution medium is circulated upward at a specific rate from an outside reservoir using a peristaltic or centrifugal pump. Dissolution fluid is collected in a separate reservoir. E.g. lipid filled soft Gelatin capsule Monday, December 07, 2015 97

98. Monday, December 07, 2015 98

99. Monday, December 07, 2015 99

100. Advantages No stirring and drug particles are exposed to homogeneous, laminar flow that can be precisely controlled. All the problems of wobbling, shaft eccentricity, vibration, stirrer position don’t exist. There is no physical abrasion of solids. Perfect sink conditions can be maintained. Monday, December 07, 2015 100

101. Dis advantages Tendency of the filter to clog because of the unidirectional flow. Different types of pumps, such as peristaltic and centrifugal, have been shown to give different dissolution results. Temperature control is also much more difficult to achieve in column type flow through system than in the conventional stirred vessel type. Monday, December 07, 2015 101

102. 3. Dialysis System Here, dialysis membrane used as a selective barrier between fresh solvent compartment and the cell compartment containing dosage form. It can be used in case of very poorly soluble rugs and dosage form such as ointments, creams and suspensions. Monday, December 07, 2015 102

103. Monday, December 07, 2015 103

104. Monday, December 07, 2015 104 12.2 Non – official dissolution method 1. Rotatory filter method 2. Rotatory flask method 3. Rotatory disk method

105. 1. Rotating Filter Method It consists of a magnetically driven rotating filter assembly and a 12 mesh wire cloth basket. The sample is withdrawn through the spinning filter for analysis. Monday, December 07, 2015 105

106. 2. Rotating Flask Dissolution Method This consists of a spherical flask made of glass and supported by a horizontal glass shaft that is fused to its sides. The shaft is connected to a constant speed driving motor. The flask is placed in a constant temperature water bath and rotates about its horizontal axis. Monday, December 07, 2015 106

107. 3 . Rotating And Static Disk Methods The compound is compressed into non disintegrating disc Mounted – One surface is exposed to medium Assumption – Surface area remains constant Used to determine the intrinsic dissolution rate Monday, December 07, 2015 107

108. Monday, December 07, 2015 108

109. 13. In vivo Dissolution Studies Techniques of In-Vivo Dissolution Testing : Product generate AUC that is plasma concentration-time curve. Simply definition bioavilable but not bioequivalent. AUC are identical within accepted statistical are stated to bioequivalent. Dissolution rate data have become the compendial standard for ensuring continuing therapeutic of various product available to pharmacist. Monday, December 07, 2015 109

110. Factor Affecting In-Vivo Dissolution 1.Gastrointestinal Motility and Presence of Food 2.Gastrointestinal pH 3.Physicochemical Nature of the Drug 4.Pharmacological Effect of Drug on GI Motility Monday, December 07, 2015 110

111. Measurement of In Vivo Dissolution: A. Indirect Techniques: 1.Loo-Riegelman analysis 2.Statistical moments 3.Deconvolution B . Direct Techniques: 1.Histroical Aspects 2.Intubation 3.Jobin et al. 4.Gamma scintigraphy 5.Perturbed angular correlation 6.Summation peak ratio 7.Neutron activation Monday, December 07, 2015 111

112. A. Indirect Techniques Loo- Riegelman Used for multi compartment system More complicated Fraction absorbed at any time t is given by: (X p ) T = is amount of drug in peripheral compartment as a function of time V c =is apparent volume of distribution K 10 =is apparent first order elimination rate constant Monday, December 07, 2015 112

113. 2.Statistical Movement It’s determine the release – rate constant (Kr) and the absorption – rate constant (Ka). Term MAT (mean absorption time) ,the mean time for drug molecule to absorbed. It composite all kinetic process of absorption, distribution, and elimination. Monday, December 07, 2015 113

114. 3.Deconvolution It is the process where output (plasma concentration profile) is converted into input ( in vivo dissolution of dosage form). The plasma or urinary excretion data obtained in the definitive bioavailability study of MR dosage form are treated deconvolution. The resulting data represent the in vivo input rate of the dosage form. It can also be called in vivo dissolution when the rate controlling step is dissolution rate. Any deconvolution procedure will produce the acceptable results. Monday, December 07, 2015 114

115. Monday, December 07, 2015 115 B. Direct technique 1.Histroical aspects: It will be of interest to mention the historical aspects of the study of in vivo dissolution. Initially ,these investigted were aimed at finding the in vivo disintegration time. Example:-Barium sulfate. 2.Intubation: Invasive technique. Routinely used in digestive physiology for feeding patient.

116. Monday, December 07, 2015 116

117. Monday, December 07, 2015 117 4. Gamma scintigraphy It is a noninvasive but involve exposing the subject to radiation. It measuring the gamma rays emitted from radionuclide. These system,two radionuclides with different peak energies can be monitored Simultaneously and independently.

118. Monday, December 07, 2015 118 5.Perturbed angular correlation To get quantitative assessment of in vivo dissolution in contrast to disintegration. Perturbed angular correlation in conjunction with external scintigraphy. 6.Summation peak ratio : The intensity of the summation peak from two gamma photon emitted successively from a radionuclide is related to the physical and chemical environment experienced by the intermediate state of the nucleus.

119. Monday, December 07, 2015 119 7.Neutron Activation These of inert excipients in the tablet is another method to study disintegration in vivo. studied radiolabeled intact tablets. It produced barium-139 and erbium-170 by irradiating the enteric-coated tablet with a neutron flux. Barium sulfate was incorporated in small quantity in the dosage form.(10mg in a 300mg tablet).

120. Methods A . Pharmacokinetic Methods These are very widely used and based on the assumption that the pharmacokinetic profile reflects the therapeutic effectiveness of a drug. These are INDIRECT METHODS . The two major pharmacokinetic methods are A. plasma level-time studies. B. Urinary excretion studies. Monday, December 07, 2015 120

121. Monday, December 07, 2015 121 Pharmacokinetic parameter 1.Peak plasma concentration (C max )- The point of maximum concentration of drug in plasma is called as peak and the concentration of drug at peak is known as peak plasma concentration. 2. Time of peak concentration (Tmax)- The time for drug to reach peak concentration in plasma is called as time of peak concentration. 3. Area under the curve (AUC) - It represent the total integrated area under the plasma level time profile and expresses the total amount of drug that comes into the systemic circulation after its administration.

122. Monday, December 07, 2015 122 B. Pharmacodynamics Method These methods are complementary to pharmacokinetic approaches and involve DIRECT measurement of drug effect on a (patho)physiological process as function of time. The two pharmacodynamic methods involve determination of bioavilability from: 1.Acute pharmacological response. 2.Therapeutic response

123. 14. Dissolution pattern Product Industry First three stages ( Initial stages) Pilot Batches (trial Batches) In vivo test In vitro test Monday, December 07, 2015 123

124. 15. In vitro study is more accepted as compared to In vivo study In vivo study are more time consuming , tedious, complex, expensive, more expenditure, use animal model , the animal model leads to toxicity. Some time error is occur waste of animal model. In case of in vitro studies are simple, rapid, reproducible, in expensive, economical, Hence in vitro study is more accepted as compared to in vivo study. Monday, December 07, 2015 124

125. 16. IV-IVC In vitro – in vivo correlation Introduction Definition- The predictive mathematical model that describes the relationship between an in vitro properties of dosageform and in vivo response of dosage form. Bioavailability T he exact rate of absorption of drug from dosage from is represented by serum concentration time curve. Amount of drug reaches to systemic circulation. Monday, December 07, 2015 125

126. Monday, December 07, 2015 126 In vitro in vivo study is important is define has the in vitro dissolution behavior of drug and in vivo bioavailability of drug . It is important to maintain the in vitro in vivo relationship. It is important to determine rate of dissolution of drug and amount of drug in systemic circulation. It is important to determine the plasma concentration of drug. New drug development studies. To determine pharmacokinetic and pharmacodynamics relationship. To determine bioavailability.

127. Objectives of IVIVC To ensure the batch to batch consistancy in physiological performance of drug product. Tool as development of new dosage form desired in vitro performance. To assist in validation or setting dissolution specification. Monday, December 07, 2015 127

128. Some of the used quantitative linear method of IVIVC Correlation based on plasma level data Here parameter used for correlating in vitro dissolution with plasma data are……. In vitro parameters % drug dissolve Rate of dissolution Dissolution rate constant In vivo parameters % drug absorbed Rate of absorption Absorption rate constant Monday, December 07, 2015 128

129. Correlation based on urinary excretions data Here dissolution parameter are correlated to the urinary excreation data. parameter s correlated are…… The amount of drug excreated unchanged in the urine Cumulative amount of drug excreted as function of time, etc. Monday, December 07, 2015 129

130. Correlation based on the pharmacological response Here an acute pharmacological effect such as LD50 ED50 in animals is corelated to any of the dissolution parameter. Monday, December 07, 2015 130

131. Levels of IVIVC These IVIVC levels have been defined and catagorised in descending order of usefulness Level A Level B Level C Monday, December 07, 2015 131

132. Level A This is highest category of correlation, it represents point to point relationship between in vitro dissolution and in vivo rate of absorption. The in vitro dissolution and in vivo absorption rate curves are superimposable The mathematical description for both curves is the same. The curves having same shape. Monday, December 07, 2015 132

133. Advantages A point to point correlation is developed. The in vitro dissolution curve serves as surrogate for in vivo performance. Any changes in manufacturing procedure or modification in formula can be justified without need of additional human study. It serves as indicating quality control procedure for predicting dosage form performance. Monday, December 07, 2015 133

134. Level B It utilises the principles of statistical moment analysis. The mean in vitro dissolution time is compared with either mean residence time or mean in vivo dissolution time. Weather such correlation is not point to point correlation since there are no of in vivo curves that will produce similar mean residence time value. Monday, December 07, 2015 134

135. Limitations It utilises all data, but is non unique as different shaped absorption /dissolution curves could result in same moment value. This correlation alone fails to justify formulation modification, manufacturing site change, excipients source change, etc. It does not justify the extremes of quality control standards. Monday, December 07, 2015 135

136. Level C It is a single point correlation It correlates one dissolution time point (i.e. t 50 % ) to one pharmacokinetic parameter such as AUC, t max , C max . This level is generally useful only as a guide in formulation development or quality control. Monday, December 07, 2015 136

137. Limitations It does not reflect the complete shape of plasma level curve which is critical factor defines the performance of controlled or sustained release products. The correlation is non-unique. Thus it can only serves as guide in formulation development and production, quality control procedure. Monday, December 07, 2015 137

138. 17. Biopharmaceutical classification system (BCS) The Biopharmaceutical Classification System was first developed by in 1995, by Amidon et al & his colleagues. Definition “The Biopharmaceutical Classification System is a scientific framework for classifying a drug substance based on its aqueous solubility & intestinal permeability & dissolution rate”. To saved time & fast screening is required so drug substances are classified on basis of solubility & permeability. This classification is called Biopharmaceutical Classification System. Monday, December 07, 2015 138

139. Factor affecting on Biopharmaceutical Classification System The Biopharmaceutical Classification System has been developed to provide a scientific approach to allow for to prediction in vivo pharmacokinetics of oral immediate release (IR) drug product by classifying drug compound based on their 1 . Solubility 2 . Permeability 3 . Dissolution Monday, December 07, 2015 139

140. Solubility Solubility It is a process in which solid can dissolved in liquid in presence of constant temperature and pressure from saturated solution.is known has solubility. It is conducted 4˚c to 37˚c Temperature. Solubility is important parameter solubility is increases rate of dissolution is increases. Solubility is directly proportional to dissolution rate Monday, December 07, 2015 140

141. Monday, December 07, 2015 141 Solubility is the ability of the drug to be solution after dissolution. The higher single unit dose is completely soluble in 250 ml or less of aqueous solution at pH 1- 6.8 ( 37˚C ). The pH solubility profile determined at 37 ± 1˚ C. In aqueous media within a pH range of 1 to 7.5 A minimum of three replicate determination of pH solubility recommended . Shake – Flask or Titration method .

142. Methods for determination of solubility Nephelometric method Turbidimetric method Direct solubility method Equilibrium solubility method Ultrafiltration Lc-Ms Method Monday, December 07, 2015 142

143. Permeability Permeability of the drug to pass the Biological membrane which is the lipophilic. Permeability is based indirectly based on the extent of absorption of a drug substance in human. Drug substance is considered to be highly permeable, when the extent of absorption in human determined to be 90% or more of administered drug or compare to in vivo reference dose. Monday, December 07, 2015 143

144. Determination of Permeability A) Pharmacokinetics studies in human 1. Mass Balance Studies 2. Absolute Bioavailability Studies B) Intestinal Permeability Method C) Instability in the GIT Monday, December 07, 2015 144

145. Determination of Dissolution Using USP apparatus I at 100 rpm or USP apparatus II at 50 rpm in 900 ml. Dissolution Media ( 900 ml ) – 0.1 N HCl or stimulate Gastric Fluid USP without enzyme. pH 4.5 buffer & pH 6.8 buffer or stimulated Intestinal Fluid USP without enzyme. Monday, December 07, 2015 145

146. Monday, December 07, 2015 146 CLASS SOLUBILITY PERMEABILITY Class – I High High Class – II Low High Class – III High Low Class – IV Low Low

147. Class I Ideal for oral route administration . Drug absorbed rapidly . Drug dissolved rapidly . Rapid therapeutic action. e.g. Metoprolol , Propranolol. Monday, December 07, 2015 147

148. Class II Ideal for oral route administration . Drug absorbed rapidly . Drug dissolved rapidly . Rapid therapeutic action. e.g. Metoprolol , Propranolol. Monday, December 07, 2015 148

149. Class III Oral route for administration . Drug absorbance is limited . Drug dissolve rapidly . e. g.- Cimitidine, Metformin. Monday, December 07, 2015 149

150. Class IV Poorly absorbed orally administration . Both solubility & permeability limitation . Low dissolution rate . Slow or low therapeutic action . e. g.- Taxol, Clorthiazole. Monday, December 07, 2015 150

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154. Monday, December 07, 2015 154

155. Class Boundaries HIGHLY SOLUBLE The highest dose strength is soluble in < 250 ml water over a pH range of 1 to 7.5. The volume estimate - a glassful (8 ounce) HIGHLY PERMEABLE When the extent of absorption in humans is determined to be > 90% of an administered dose. RAPIDLY DISSOLVING When > 85% of the labeled amount of drug substance dissolves within 30 minutes using USP apparatus I or II in a volume of < 900 ml buffer solutions. Monday, December 07, 2015 155

156. 18. Biowaiver The in vivo bioequivalence testing Definition It is an exemption from conducting human bioequivalence studies when the active ingredients meet certain solubility and permeability criteria in vitro and when the dissolution profile of the dosage form meets the requirements for an IR dosage form. Monday, December 07, 2015 156

157. Criteria of Biowaiver Rapid and similar dissolution. High solubility. High permeability. Wide therapeutic window. Excipient used in dosage form are same as those present in approved drug product. Monday, December 07, 2015 157

158. Application Of Biopharmaceutical Classification System To predict in vivo performance of drug product using solubility and permeability measurements. Aid in earliest stages of drug discovery research. To use in bio waiver considerations. For research scientist to decide upon which drug delivery technology to follow or develop. Also for the regulation of bioequivalence of the drug product during scale up and post approval . Monday, December 07, 2015 158

159. 19. Dosage from conducted dissolution study 1. Immediate release tablet (conventional tablet) Dissolution apparatus – Type 1 and Type 2 (USP) Temperature - 37±0.5˚ C Time – 30 min Time of interval – 5, 10, 15, 20, 25, 30. Media – PH 1.2 Acidic Buffer, PH 4.5 Acetate buffer, PH 5.8 Phosphate buffer. (depending upon tablet) Rpm – 75 -100 rpm Volume – 900 ml Monday, December 07, 2015 159

160. Monday, December 07, 2015 160 Procedure – The tablet was added into cylindrical vessel containing 1000 ml dissolution media having rpm 75 and tem. 37±0.5 ˚ C . Dissolution of tablet was conducted 30 min , in 5 min. of interval , after 5 min 5 ml sample was removed and appropriate quantity of sample take absorbance by using U.V. spectroscopy technique and determine rate of dissolution of tablet . 2. Sustained release tablet Dissolution apparatus – Type 2 (USP) Temperature - 37±0.5˚C Time – 180 min Media – PH 1.2 Acidic Buffer, PH 6.8 Phosphate buffer. Rpm – 75 – 100. Volume – 900 ml.

161. Monday, December 07, 2015 161 Procedure - The tablet was added into cylindrical vessel containing 1000 ml PH 1.2 Acidic media having rpm 75 for next two houres and tem . 37±0.5 ˚ C . Dissolution media was changes tablet was added in to PH 6.8 Phosphate buffer for next one hour for 10 min of interval. after 10 min 5 mi sample was removed and appropriate quantity of sample take absorbance by using U.V. spectroscopy technique and determine rate of dissolution of tablet . 3. Capsule Dissolution apparatus – Type 2 (USP) Temperature - 37±0.5˚C Time – 180 min Media – PH 1.2 Acidic Buffer, PH 6.8 Phosphate buffer. Rpm – 75 – 100. Volume – 900 ml.

162. Monday, December 07, 2015 162 Procedure - The Capsule was added into cylindrical vessel containing 1000 ml PH 1.2 Acidic media having rpm 75 for next two hours and tem. 37±0.5˚C . Dissolution media was changes Capsule was added in to PH 6.8 Phosphate buffer for next one hour for 10 min of interval. after 10 min 5 mi sample was removed and appropriate quantity of sample take absorbance by using U.V. spectroscopy technique and determine rate of dissolution of Capsule . 4 . Suppositories Dissolution apparatus – Type 1 (USP) Temperature - 37±0.5˚C Time – 60 min Time of interval – 10, 20, 30, 40, 50, 60. Media – PH 7.4 Phosphate buffer. Rpm – 50 – 75 rpm Volume – 900 ml .

163. Monday, December 07, 2015 163 Procedure – The Suppository was added into cylindrical vessel containing 1000 ml dissolution media (PH 7.4 Phosphate buffer) having rpm 75 and tem. 37±0.5˚C . Dissolution of Suppository was conducted 60 min , in 10 min. of interval , after 10 min 5 ml sample was removed and appropriate quantity of sample take absorbance by using U.V. spectroscopy technique and determine rate of dissolution of Suppositories .

164. 20. Reference 1. Fonner . D. E, Banker. G. S., Granulation & Tablet Characteristics, In Pharmaceutical Dosage Forms: Tablets. Vol. 2. Edited by H. Lieberman & L. Lachman , Dekker, New York, 1982, p. 202 2. Leon Lachman , Herbert. A. Lieberman, The Theory and Practice of Industrial Pharmacy, 3 rd edition, Varghese Publishing House, Bombay, 1991, pp. 301-303 3. Brahmankar . D. M. , Sunil Jaiswal. B, Biopharmaceutics and Pharmacokinetics—A Treatise, 1 st edition, Vallabh Prakashan, New Delhi, 2006, pp. 19-25 4. Alfred Martin , James Swarbrick, Physical Pharmacy, 3 rd edition, Varghese Publishing House, Bombay, 1991, pp. 408-412 5. Florence , Alexander T. and Siepmann, Juergen (2009). Modern Pharmaceutics Application and Advance . Volume 2 nd , 5 th edition. Informa Healthcare, Page no. 34 – 35. 6. Benet , Leslie and William, Addics (ND). Application of the Biopharmaceutical Classification System . 7. www.eufeps.org . (Access Time - 12.45 A M Date- 05 - 12- 2015). 8 . Budhwaar , V. And Nanda, A. (2012). The Biopharmaceutics Classification System : Present Status and Future Prospective. International Research Journal of Pharmacy. 3(9), Page No. 7 – 10. Monday, December 07, 2015 164

165. Monday, December 07, 2015 165 9 . Dr . Tipnis H.P. and Dr. Bajaj Amrita, Principles and applications of Biopharmaceutics and Pharmacokinetics , 1 st edition 2002, reprint 2005, career publication, Page no. 332-340. 10. Umesh v. banakar ,pharmaceutical dissolution testing, volume 47,marcel dekkar, inc., new york,p.p.209-237. 11. Dissolution . (n.d.) American Heritage® Dictionary of the English Language, Fifth E).dition. (2011)

166. Monday, December 07, 2015 166