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![FACTORS RELATED TO DRUG SUBSTANCE
Dissolution - Solubilization of drug into dissolution medium
Control – affinity b/n solid & disso lutionmedium, as diffusion of drug into
bulk liquid media
Noyes and Whitney equation
dm/dt = K (Cs-Ct)
(Cs-Ct) – conc gradient b/n diffusion layer & bulk soln
Brunner & Tolloczko incorporated S
dm/dt = K’ x S (Cs-Ct)
S – Surface area, K’ – constant to chemical subs
Brunner expanded scope – included Nernst’s theory
Dc/dt = [DS/Vh] x (Cs-Ct)
D – Diffusion coefficient, h – thickness of diffusion layer, V –dissolution
volume
Drug dissolution – inflUenced by solubility, diffusivity, SA and solution
hydrodynamics
8](https://image.slidesharecdn.com/invitrodrugproductperformance-230714041538-7df2358a/75/In-Vitro-Drug-Product-Performance-ppt-8-2048.jpg)
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In Vitro Drug Product Performance.ppt
- 1. 1 IN VITRO DRUG PRODUCTPERFORMANCE Department of Pharmaceutics
- 2. Introduction Importance &utilization of in vitro characterization – solid orals Relation – factors affecting in vitro drug release Intrinsic characters of drug, drug product, mfg process, dissolution test method Practical issues and applications 2
- 3. Importance of invitro drug product characterization Modern solid orals – high quality, reliable performance characteristics Careful selection, QC, GMP Variables – Pdt appearance, potency, stability and dissolution Application of research methodologies Use of latest instruments, equipments, techniques – Complex Characterization – API potency, uniformity, drug release rate Data – Imp for FD, comparability assessment, QA & QC 3
- 4. Importance of invitro drug product characterization Tests – Based on monographs, general chapters, guidance docs – FDA/CDER Content & consistency – Potency/assay, content uniformity/ wt variation After intake of solid orals Disintegration, dissolution, solubilization Permeability across membranes of GIT Critical steps In vitro dissolution predict in vivo performance - Low solubility drugs, modified release drugs - Drug release – RL Step for in vivo absorption 4
- 5. Solid orals -Types • Tablets Oral (Regular) Effervescent Chewable Orally disintegrating Sublingual Buccal Lozenges, troches, tablet tricurates Dispensing tablets, solution tablets etc • Capsules Hard Gelatin Capsules Soft Gelatin Capsules 5
- 6. Solid orals -Release • Immediate release –Drug promptly released after administration • Modified release Delayed release (Enteric coated)- retard the release of active until it passes stomach Protect gastric mucosa – drug irritation Limit exposure in stomach – acid labile Have target release – enhance absorption Extended release (CR, SR) – active available for extended period of time SR, CR and repeat action – lengthen dosing interval, reduce frequency Enhance patient convenience, compliance, increased therapeutic effectiveness, minimize toxic effects 6
- 7. Factors affecting In vitrodrug product dissolution Steps Wetting & penetration of dissolution medium – Dosage form Disintegration/ deaggregation Solubilization of drug substance into solution Factors Factors related to drug substance Formulation factors Manufacturing process factors Dissolution/ drug release test conditions 7
- 8. FACTORS RELATED TODRUG SUBSTANCE Dissolution - Solubilization of drug into dissolution medium Control – affinity b/n solid & disso lutionmedium, as diffusion of drug into bulk liquid media Noyes and Whitney equation dm/dt = K (Cs-Ct) (Cs-Ct) – conc gradient b/n diffusion layer & bulk soln Brunner & Tolloczko incorporated S dm/dt = K’ x S (Cs-Ct) S – Surface area, K’ – constant to chemical subs Brunner expanded scope – included Nernst’s theory Dc/dt = [DS/Vh] x (Cs-Ct) D – Diffusion coefficient, h – thickness of diffusion layer, V –dissolution volume Drug dissolution – inflUenced by solubility, diffusivity, SA and solution hydrodynamics 8
- 9. Solubility ofdrug substance Dissolution associated with solubility High solubility – high dissolution rates Comp with “ionizable groups” – depend on pH of disso med and pKa comp Solubility check – eq sol method Metastable polymorphs – converted – forms Dynamic method – kinetic solubility Dose/solubility ratio – fluid vol reqd If > 1L, in vivo disso – problem Eg: Griseofulvin- aq sol 15 µg/ml, 500 mg, ratio of 33.3 L dissolution/solubility limited oral absorption 9
- 10. Polymorphism Drug– physical forms, solid-state polymorphism Polymorphism – more crystalline forms, hydrate forms, amorphous phases Change in lattice energy- diff solubility & dissolution Differences in solubility crystalline polymorph – less or several folds hydrates – less solubility than anhydrous forms amorphous forms – > 100 times of cry comp Eg: CPM – A & B B greater oral abs than A 10
- 11. Salt factorand pH of diffusion layer Organic salt > water soluble than unionized molecule – increased dissolution Most drugs – salts of Na/K & HCl Considered during FD Salts of free bases > soluble than parent unionized molecule – change in use. Eg: Naproxen Parent unionized – rheumatoid/osteo arthritis Na Salt – More soluble - Post partum pain 11
- 12. Surface areaand particle size Dissolution – related to SA Decrease in particle size – increased SA, increased dissolution Micronized drugs – better dissolution Eg: Glyburide, Griseofulvin 12
- 13. FORMULATION FACTORS Excipients– have effects on formulation ADVANTAGES Immediate release – excipients enhances dissolution Disintegrants – Crosscarmellose Na, Na starch glycolate – deaggregation, more SA Surfactants – SLS, polysorbates – increase disso rates Micelle formation – increase sol of hydrophobic drugs Facilitates wetting, decreases ST, inc large drug-solvent surface interface 13
- 14. FORMULATION FACTORS DISADVANTAGES Drugshouldn’t bind to excipient – insoluble metal chelate – alters dissolution Lubricants – stearates – hydrophobic (<1%) – reduces wetting & disso Gelatin cap –prone to cross link – free aldehydes or keto groups – pellicle forms – decreases dissolution Modified release forms Absorption windows – hydrophobic/philic, ion exchange resin, osmotic pump, coating Factors – properties of API, type of release device, excipients, desired drug release profile 14
- 15. MANUFACTURING PROCESS FACTORS Mfg variables affect dissolution rates Spray dried/ melt extrusion of API with PVP – stable – enhanced disso Method of granulation – API character Problems of mfg process Over mixing of lubricants, more compression pressure Modified release – Process- defined, robust, reproducible batches Each process to have well defined end points 15
- 16. DISSOLUTION/ DRUG RELEASETEST CONDITIONS Variables Dissolution medium Volume pH Rotation speed Others Instrumentation Assay methods Valid measurements & actual, accurate representation 16
- 17. In vitro drugperformance evaluation DISINTEGRATION TEST Described in USP General chapter <701> Disintegration Its appropriate – if relation established with dissolution Or, DIS is discrimination with dissolution Official apparatus – USP basket rack assembly – Immediate release ICH Q6A – decision tree for applying disintegration test If dissolution is rapid (NLT 80% in 15 min at pH 1.2, 4.0 & 6.8) & drug soluble in physiological range – disintegration test meaningful Drug – highly soluble – if highest dose soluble in 250ml or less aq. Media over pH 1.2-6.8 250 mL – typical BE study protocol – fasting subjects (8 fl. oz) 17
- 18. Dissolution test Immediate releasesolid oral dosage forms Quantitative measure of drug that dissolve from dosage form to dissolution medium under std apparatus & procedure FDA – Dissolution testing of Immediate release solid oral dosage forms Reqd for all solid oral dosage forms for pdt approval ICH Q6A – Dissolution test conditions, tolerances Test conditions – sensitive & discriminatory measure of drug pdt performance Dissolution data – support – PA changes (mfg/ form), waive BE studies* * certain conditions only 18
- 19. Dissolution test Immediate releasesolid oral dosage forms Apparatus Media Tolerance 19
- 20. Dissolution test -APPARATUS Immediate release solid oral dosage forms USP General chapter <711> Dissolution Apparatus I (basket), II (paddle) Basket – 100 rpm (cap), 50 rpm (tab) Rotation rate increases, dissolution rate increases ICH Q6A – decision tree for deviation of suitable dissolution test conditions and tolerances USP apparatus III – for immediate release excluding extended release forms Apparatus 4 & 7 – extended release products (tab/cap) 20
- 21. Dissolution test Immediate releasesolid oral dosage forms USP APPARATUS USP Apparatus Description Rotational speed Dosage form 1 Basket 50-120 IR, DR, ER 2 Paddle 25-100 IR, DR, ER 3 Reciprocating cylinder 6-35 dpm IR, ER 4 Flow through cell N/A ER & poorly soluble API in IR 7 Reciprocating disk 30 cpm ER 21
- 22. Dissolution test –MEDIA Immediate release solid oral dosage forms Media – based on physico chemical properties of drug & dosage form Mimic physiological conditions pH range from 1.2 to 6.8 selected Common media – 0.1 N HCl, pH 4.5 acetate buffer, pH 6.8 phosphate buffer API Weak acids – DR increases with increases in pH Weak bases – DR decreases with increases in pH Poor aq. solubility – Large dissolution medium Surfactants may be used – sink conditions, inc solubility, DR – by reducing interfacial tension, micelle formation Adding ionic salts – increases DR Hydroalcoholic solns adding – not preferred 22
- 23. Dissolution test –MEDIA Immediate release solid oral dosage forms HGC/SGC – enzymes may be added – prevents pellicle formation Air bubbles – removed by deaeration method described in USP <dissolution> or other methods Temperature – 37 + 0.5°C New research, bio-relevant media Predict dissolution of poorly soluble drugs, plasma levels of lipophilic drugs 23
- 24. Dissolution test –TOLERANCE Immediate release solid oral dosage forms DT acceptance (tolerance) – Quantity (Q) that is dissolved within a specified time interval Given as % of labeled claim (not assay) of API in dosage form 75-80% of drug to be dissolved in set time (15-60 min) Dissolution test results evaluated by acceptance table in USP <711> 711 describes criteria for mean and individual sample dissolution results S1, S2, S3 specifying 6, 12 & 24 samples tested 24
- 25. Dissolution test –TOLERANCE Immediate release solid oral dosage forms Q should be used “as is”, not confused with “Q + 5%” as specified in stage I (S1) BE purpose – stage II (S2) used – 12 samples Dissolution tolerances established based on profiles obtained from drug product on which BA/BE studies were done Generic immediate release product – meets USP specs If no USP specs – product to meet or exceed in vitro disso performance of RLD Drug solubility, permeability, DR, pharmacokinetics – considered for dissolution test specs – for product similarity/ equivalence 25
- 26. Dissolution test Modified releasesolid oral dosage forms Described in USP General chapter <724> Drug release Drug release test same as dissolution test, but applied for modified release dosage forms not for IR FDA’s recommendations BA & BE studies for orally administered drug products- General considerations and extended release oral dosage forms: Development, evaluation and application of in vitro/ in vivo corelation Sample size – 6 to 24 units BE studies – 12 dosage units Different drug/ mfr – unique drug release, but need not use the tests approved for testing RLD/ other mfr Unjustified tests are not encouraged 26
- 27. Dissolution test -APPARATUS Modified release solid oral dosage forms USP <724> – equipment specs, operational std for app 3, 4 & 7 in addition to app 1 & 2 App 1 & 2 – preferred If specific advantage over app 1 & 2 – others can be used Non official apparatus - discouraged 27
- 28. Dissolution test –MEDIA Modified release solid oral dosage forms Same as used in immediate release dosage forms No provision for adding enzymes 2 stage testing – For DR (enteric coated), solid orals 1st in 0.1 N HCl for 2 hr, next in pH 6.8 buffer Acid stage and buffer stage – acceptance as per USP <724> 28
- 29. Dissolution test –TOLERANCE Modified release solid oral dosage forms Release tolerance – based on in vitro drug release performance on the bio-study lots Tolerance – minimum of 3 time points within labeled dosing interval 1st tolerance – set at 1 h ensure against “dose dumping” Subsequent time points – set as ranges, final time point – min value of label claim (NLT -80%) Tolerances as per acceptance table 4 in <724> 3 levels described as for immediate release drug products 29
- 30. Dissolution/ drug releaseprofile comparisons FDA guidance request submission of comparative multi- point dissolution profile data in addition to meeting a single point tolerance (Q) Profile comparison approaches – developed & evaluated by agency • Model-dependent • Model-independent-multivariate • Model-independent-index Useful to compare dissolution profiles of drug product lots, evaluate effects of scale-up and PA changes 30
- 31. Model dependant approach Profile similarity evaluated using suitable mathematical model to describe dissolution data Recommended for dissolution “data rich” conditions Similarity region Statistical distance Confidence region Compare confidence region & similarity region 31
- 32. Model independent “Multivariate” approach •Dissolution values are directly compared – no model / creating parameters • Each dissolution measurement – considered as variable, corelated to adjacent time point • Statistical distance – accounted for mean dissolution differences and their variance, covariance matrix • Later, confidence region is calculated around the statistical distance. 32
- 33. Model-independent-index approach Profilesare compared wrt prior defined index Several indices Rescigno (1992) & Rho, Rho-m, Delta-a, Delta-s. Fit factors – f1 & f2 – Moore & Flanner (1996) “FDA guidances” recommend f2, known as “similarity factor” f1 & f2 – measure overall difference and similarity b/n two profiles Greater the value of f2 or smaller the value of f1 – more similar are the 2 profiles f2 value b/n 50 to 100 suggests less than 10% global or overall diff b/n 2 disso profiles 33
- 34. Applications of invitro dissolution 1. Product development IVD aids in guiding the selection of prototype formulations, optimum level of ingredients to achieve drug release profiles (ER) Guides in selection of “market image” product to be used in BA/BE studies 34
- 35. Applications of invitro dissolution 2. Quality assurance Dosage form should possess acceptable in vitro, in vivo BA/BE characters Dissolution test method and acceptance criteria devised based on dissolution testing of bio-lots Depends of drug characteristics For future lots, dissolution used to assess lot-to-lot performance of drug pdt – continued assurance 35
- 36. Applications of invitro dissolution 3. Product stability IVD – assess pdt quality, stability & shelf life Aged pdt – characteristics changed, hence IVD also changes Eg: Change in moisture level – alters hardness of tablet – also IVD In polymorphs – transformations to stable polymorphs – less soluble, IVD HGC – aldehyde-amino cross linking – pellicle formation – altered IVD IVD done throughout the shelf life – provides assurance of product performance till the expiry 36
- 37. Applications of invitro dissolution 4. Comparability assessment IVD used to assess the impact of pre and PA changes to product “SUPAC guidelines” – nature and extent of changes, describes the use of either a single point or disso profile comparison to evaluate changes Required to ensure continued performance equivalency and pdt similarity 37
- 38. Applications of invitro dissolution 5.Waivers of in vivo BE requirements May be used to waive in vivo BA/BE in following 5.1 Formulation proportionality BA/BE studies conducted on 1 strength, BA/BE on other lower strengths of same products – waived, if Proportionally similar – active & inactive, same dissolution profiles Formulation proportionality – 2 types 1. constant proportion – A & IA changed proportionally across strength 2. constant weight – total weight is held constant across strengths – for low dose drugs 38
- 39. Applications of invitro dissolution 5.2 Biopharmaceutics classification system (BCS) I – High solubility, high permeability II - Low solubility, high permeability III- High solubility, low permeability IV - Low solubility, low permeability Highly soluble drug – highest dose in < 250 ml aq media, pH 1.2 to 6.8 Highly permeable – extent of abs (AUC) is > 90% of an administered dose Rapidly dissolving product – IR, NLT 85% of labeled amount dissolves within 30 min in type I-100 rpm or type-II-50 rpm, vol 900 ml or less in each of these: acidic media, pH 4.5, pH 6.8 Class I – HS, HP, rapidly dissolving – RLS is gastric emptying For class I BE studies can be waived Absorption calculated based on solubility, trans-intestinal absorption rate constant, SI water volume and transit time 39
- 40. Applications of invitro dissolution 5.3 In vitro/ In vivo correlations Correlation done by techniques like de-convolution Technique predicts in vivo dissolution and absorption and establishes the IVIV relation Levels of correlation – A, B or C Done for BCS Class II drugs & ER pdts If IVIVC established, BE may be waived Models to be identified based on objective criterion for in vitro/ in vivo correlation analysis 40
- 41. Limitations of invitro dissolution Has several utilities & advantages, but limitations cant be overlooked Precision, accuracy of DT depends on several subtle operational controls Stirring element eccentricity, agitation alignment, torsional vibration, dosage form position, sampling position, dissolved gases, flow patterns, heat transfer etc Recent study – diff tab positions – diff results Strict control on these subtle factors – assure reliable & reproducible test results Relevance – imp limitation of dissolution In absence of suitable IVIVC, dissolution # in vivo IR ptds – Class I & II, DT is overdiscriminating, bcoz oral absorption is limited by gastric emptying or int permeation 41
- 42. Limitations of invitro dissolution IR pdts –Class III & IV, single point DT is non-discriminating- unable to detect lots with poor in vivo performance If IVIVC – est for pdt, limited value as “Product specific” - cant extend to other pdts Despite of limitations – DT is most imp and useful in vitro test for assuring pdt quality Limitations – help in judicious conclusion about the significance/ insignificance of DT results – pdt performance Recognize and develop meaningful and useful DT methodology 42
- 43. Glance……. In vitrocharacterization – essential for in vivo performance of product In vitro testing – useful during pdt development, QA & control, pdt stability testing, assess comparibility Useful in getting waivers for pdts meeting BCS Class I requirement or when meaningful IVIVR is established Modern developments for in vitro testing – fiber optics (detect drug concn. in disso med), application of artificial neural network for disso prediction and Process Analytical Technology (PAT) 43