Dissolution Considerations for Novel Immediate Release Formulations Presented by Syed anees ahmEd B. Pharm. Rameshwaram Institute of Technology And Management, Lucknow
INTRODUCTIONNovel Immediate Release Dosage FormsSubjected to Routine Tests Content Uniformity Weight Hardness Friability DisintegrationTHE MOST OFTEN TEST ASSOCIATED WITHASSESSMENT OF IN VIVO PERFORMANCE IS DISSOLUTION TEST
DISSOLUTION TESTIntegral component of new drugs applications toregulatory bodies worldwide. Classic vs. modern use of dissolution testing. "Classic" use of dissolution tests: Quality Control. "Modern" use of dissolution tests: to simulate the in vivo release behavior of the dosage form with a view to in vitro-in vivo correlation.
DECISION TREE FOR DISSOLUTIONTEST DESIGN1. Classify the compound according to BCS.2. Choose an appropriate medium. Class 1, 3: use the most simple medium. Addition of surfactants is unnecessary. Class 2, 4: biorelevant media warranted. SGFsp + surfactant, FaSSIF ( fasted state ). Ensure , milk, FeSSIF ( fed state ). SGFsp / SIFsp + suitable surfactant.
3. Choose an appropriate medium volume. Volumes for the fasted state will be lower than volumes for the fed state.4. Choose an appropriate test duration. Class 1, 3: short test (up to 30 min). Class 2, 4: test duration depends on: - region of gut. - fasted or fed state.5. Apparatus: USP II for IR products mainly used. USP I .6. RPM: 50 or 75 rpm is usually suitable.
WHICH FACTORS CAN LIMITBIOAVAILABILITY AFTER ORALADMINISTRATION? Factors can determine the rate and extent of drug absorption following oral administration.1. Slow release of the drug from the dosage form.2. Instability of the drug in the GI tract.3. Poor permeability of the GI mucosa to the drug.4. First-pass metabolism of the drug in the gut wall or liver.
Biopharmaceutics Classification Scheme can be usedas a guide to determine whether an IVIVC can beexpected for IR product.Table 1 The Biopharmaceutics Classification Scheme(BCS) Class 1 Class 2 High solubility Low solubility Good permeability Good permeability e.g. Acetaminophen and e.g. Antifungals, Steroids, Meteprolol NSAIDs, CV agents and Antidiabetics Class 3 Class 4 High solubility Low solubility Poor permeability Poor permeability e.g. Antiviral acyclovir, Aminoglycoside neomycin
SELECTION OF DISSOLUTIONTEST MEDIA BASED ON THE BCSA. Class 1 Substances dose (mg) D/S = aq. Solubility (mg/mL)- It yields the volume of liquid required to dissolve the entire dose of the drug.- The ratio exceeds the actual volume of GI fluids dissolution + absorption will not be complete.- The FDA uses a D/S of 250 mL. for compounds with good solubility.- D/S exceeds 250 mL. dissolution will be limiting factor.
The release of drug is not limiting factor to absorption.It limited by non dosage-form-related factors, such asgastric emptying.U.S. ( FDA ) recommends in a simple medium 85%or more of the drug to be released within 30 min. for IRdosage form of class 1 drugs.SGF without enzyme suitable of many IR dosage formof class 1 drugs.For some capsules SGF + Enzyme ( pepsin ) ensuredissolution of the shell.SIF without enzyme suitable for weak acid.FaSSIF and FeSSIF are unnecessary for dissolution ofclass 1 drugs.
120 100 80% Release 60 40 FaSSIF FeSSIF 20 0 0 10 20 30 40 50 60 Time ( min ) Fig.1 Dissolution of acetaminophen ( Panadol) tablets in FaSSIF, and FeSSIF at 100 rpm in a paddle apparatus.
B. Class 2 SubstancesCompounds can be defined as being poorly soluble whentheir dissolution rate is the limiting factor to their oralbioavailability.Suitable, biorelevant media :1. SGFsp + Surfactant SGFsp + Surfactant suitable for weak bases. e.g. of class 2 bases Ketoconazole and Dipyridamole. In the fasted state, the absorption of both compounds is highly dependent on gastric pH. Hypochlorhydria as a result of cotherapy with gastric acid blockers is associated with very poor absorption. The presence of surfactant in the gastric fluids may play a role in the wetting and solubilization of poorly soluble acids in the stomach.
Table 2 Sample Composition for SGFsp with Surfactant.HCl 0.01 – 0.05 M Triton X–100 0.01% NaCl 0.2% Water qs 1L
The influence of the surfactant Triton X- 100 on the release rate of several albendazole products in SGFsp. 100 100 80 80% release % release 60 60 40 40 Zentel Zentel Alben Alben 20 Albendazol MK Albendazol MK Zirkon 20 Zirkon 0 0 0 20 40 60 80 100 120 0 20 40 60 80 100 120 (a) Time ( min) (b) Time ( min) Fig.2 Dissolution profiles of various albendazole products in acidic media (SSF sp ): upper panel without and lower panel with 0.1% Triton X-100
2. Ensure and Milk as Dissolution Media Mechanisms by which Ensure and milk can improve drug solubility include solubilization of the drug in the fatty part of the fluid. Disadvantage: Difficulties in filtering and separating the drug from the medium make these media unsuitable for routine quality assurance testing.
3. FaSSIF and FeSSIF Table 3 and 4 Show the compositions of these media, FaSSIF and FeSSIF. Table 3 Composition of FaSSIF. KH2PO4 3.9 g Na taurocholate 3 mM Lecithin 0.75 mM KCl 7.7 g NaOH qs pH 6.5 Distilled water qs 1L Table 4 Composition of FeSSIF Acetic acid 8.65 g Na taurocholate 15 mM Lecithin 3.75 mM KCl 15.2 g NaOH qs pH 5 Distilled water qs 1L
These two media are useful for:1. Forecasting the in vivo dissolution of poorly soluble drugs.2. Assessing potential for food effects on in vivo dissolution. The dissolution rate of a poorly soluble drug is better in FaSSIF & FeSSIF than simple aqueous buffers because of the increased wetting of the drug surface and micellar solubilization of the drug by the bile components. e.g. Griseofulvin, Digoxin, Diazepam, Cyclosporine, Pentazocine and Danazol.
Dissolution Behavior of Various Class 2 Substances in the Different Media Ketoconazole 120 180 80 % release 60 40 SGFsp FaSSIF 20 FeSSIF 0 0 20 40 60 80 100 120 Time (min) Fig. 3 Dissolution profiles of ketocanazole in various media.Dissolution is quickest under SGFsp, No dissolution in FaSSIF, Important site of dissolution in FeSSIF.
Mefenamic acid 40 FeSSIF 30 FaSSIF SIF % Release 20 10 0 0 10 20 30 40 50 60 Time ( min ) Fig. 4 Dissolution profiles of mefenamic acid in various media.Dissolution rate in FaSSIF & FeSSIF were similar,and agreed with the lack of influence of food on theabsorption.
Troglitazone 80 70 60 50 Water % release FaSSIF 40 FeSSIF 30 20 10 0 0 20 40 60 80 100 Time ( min ) Fig. 5 Dissolution profiles of troglitazone in various media.Dissolution enhanced in FeSSIF compared withFaSSIF .
Use of synthetic Surfactants inDissolution MediaFor routine quality assurance, we use syntheticsurfactant system instead of the bile components,because:1. Their purity.2. Time and effort required.e.g. SLS, Tweens, or other.The role here depend on the type and concentration.
4. Hydroalcoholic Mixtures as Dissolution Media Popular for poorly soluble drugs. There advantage over the use of surfactants: 1. They dont tend to foam. 2. A wide range of pH values can be used without affecting the surface tension properties of the medium. 3. The solubility of some drugs is more influenced by alcohol than by surfactant.
C. Dissolution Tests for Class 3 Substances Class 3 substances fail to achieve complete bioavailability because of their poor membrane permeability. Simple aqueous can be used for quality assurance dissolution testing of IR products. The membrane permeability is a limiting factor to the absorption.
D. Dissolution Tests for Class 4 Substances Because of poor solubility with poor permeability they dont approach complete bioavailability. Chlorothiazide is an example of a borderline case between class 3 and 4 behavior. SGFsp and SIFsp + surfactant is used to assure that complete release of the drug is possible.
DURATION OF DISSOLUTIONTESTDrug best absorbed from Test duration of up to 4 h.the small intestine in thefasted state.Drug best absorbed from Test duration of up to 6 h.the small intestine in thefed state.Compound is to be Tests as long as 8 – 10 h.absorbed well from thecolon.
DISSOLUTION EQUIPMENTApparatusUSP I (basket) and USP II (paddle) are the apparatusesmost often used for IR dosage forms.Selection of Agitation Rate The most often used apparatus for IR dosage forms is USP II. Rotation speed is too low low rates of dissolution. Rate of rotation is too fast no discriminate between acceptable and not acceptable batches. Rotational speed 50 – 100 rpm paddle method. Rotational speed of up to 150 rpm basket method.
REFERENCES Galia E. et al. Evaluation of various dissolution media for predicting in vivo performance of class I and II drugs. Pharm Res. (1998) 15:698-705. United states pharmacopeia 24 and National formulary 19. Rockville, MD:United states Pharmacopeial convention,1999. Nicolaides E. et al. Forcasting the in vivo performance of four low solubility drugs from their in vitro dissolution data. Pharm Res. (1999 ) 16:1877- 1883. Young MA. et al. improvement in the gastrointestinal absorption of troglitazone when taken with or shortly after, food. Br J Clin pharmacol( 1998 ) 45: 31-35.
Dressman JB. et al. Dissolution testing as aprognostic tool for drug absorption : immediaterelease dosage forms. Pharam Res. ( 1998 ) 15:11-22.Lindenberg M. et al. Classification of orallyadministrated drugs on the World HealthOrganization Model list of Essential Medicinesaccording to the biopharmaceutics classificationsystem. Eur. J. Pharm. Biopharm. ( 2004) 58: 265-278.Dressman J.B. et al. Dissolution testing as aprognostic tool for oral drug absorption : ImmediateRelease Dosage form. Pharmaceuticals Res. (1998)15: 11-21.Rinaki E. et al. Quantitative biopharmaceuticsclassification system : The central role ofDose/Solubility ratio: Pharm. Res. ( 2003) 20:1917-1923.