ENCLOSURE-I



ENCLOSURE-I

6. BRIEF RESUME OF INTENDED WORK

6.1 Need of the study

Dissolution testing is an official test used by pharmacopeias for evaluating drug release of solid and semisolid dosage forms. Dissolution tests were first developed to quantify the amount and extent of drug release from solid oral dosage forms including immediate/sustained release tablets and capsules1. More recently, dissolution has become important in testing drug release of dosage forms such as powders, chewable tablets, buccal and sublingual tablets, chewing gums, soft gelatin capsules, suppositories, transdermal patches, aerosols and semisolids1. Dissolution testing is routinely used in Quality Control (QC) and Research & Development (R&D). The focus of dissolution testing in QC is batch to batch consistency and detection of manufacturing deviations. For QC purposes, the test should be designed to demonstrate that the dosage forms were manufactured according to specifications and all critical manufacturing steps result in a consistent product. In R&D the focus of dissolution testing is shifted to provide some predictive estimates of the drug release in respect to the in vivo performance of a drug product.

A dissolution test is an in vitro analytical test used for assessing expected drug release characteristics of pharmaceutical products in humans, in particular, of solid oral dosage forms, such as tablets and capsules. The rationale for conducting these tests is that, for a product to be therapeutically effective, the drug (active pharmaceutical ingredient or API) must be released from the product and should generally be dissolved in the fluids of the gastrointestinal (GI) tract. The API in solution form facilitates the absorption of the drug from the GI tract into the systemic (blood) circulation to reach its desired target (site of action) to exert its effect. Therefore, a dissolution test could be considered a critical step for assessment of quality of product batches, bridging to safety and efficacy aspect.

Dissolution methods are validated to ensure they are suitable for their intended use and give accurate and reliable data. Validation of a dissolution method typically involves validation of the end analysis method for specificity, precision, linearity, accuracy and range. Dissolution tests employed as quality assurance/control tests to monitor potential changes in product formulation and/or manufacturing attributes. From the method development and validation aspect, a dissolution method is treated like another analytical procedure, such as spectroscopic or chromatographic (HPLC and/or GC). Therefore, method development and validation appear to be commonly based on such performance evaluation parameters as precision, linearity, repeatability, reproducibility, limit of quantitation, etc. Certainly, these are important and critical parameters for dissolution testing.

In the present study an attempt will be made to develop and validate new dissolution method for few newer antiretroviral drugs in solid dosage forms.

ENCLOSURE- II

6.2 Review of literature

Silvia HM et.al.,2 established and validated a dissolution test for Diacerhein capsules. They developed new 0.75% of sodium lauryl sulphate. The dissolution condition was carried out dissolution medium for the study viz., 900 ml of sodium phosphate buffer pH 7.0 with using a basket apparatus at a stirring rate of 50 rpm. The drug release was evaluated by UV Spectrophotometric method at 258 nm. Further the method was validated to meet requirements for a global regulatory filing. The validation included specificity, linearity, precision and accuracy, in addition, filter suitability and drug stability in medium were also demonstrated.

Sean SJ et.al.,3 validated a dissolution method with high performance liquid chromatography (HPLC) analysis for an immediate release low dose tablet formulation. The method was validated to meet requirements for a global regulatory filing and this validation included specificity, precision, linearity, accuracy and range. Validation of precision included an intermediate precision study using an experimental design in order to satisfy Japanese regulatory requirements. In addition, filter suitability, standard and sample solution stability and method robustness were also demonstrated. A statistical design of experiments was used for the robustness evaluation of both the dissolution method and the HPLC analysis method. All results were acceptable and confirmed that the method is suitable for its intended use.

Paraskevas DT et.al.,4 optimized and validated a dissolution test for Famotidine tablets using flow injection analysis (FIA). The effect of dissolution parameters such as pH, medium and stirring speed was studied, while the ruggedness of the procedure was validated. All measurements were performed using a simple direct spectrophotometric flow injection assay (λmax = 265 nm) that has also been optimized and fully validated in terms of linearity, limit of detection, precision, selectivity and accuracy. The dissolution results during quality and stability control of two batches of Famotidine tablets obtained by the flow injection method were in good agreement with high-performance liquid chromatography (HPLC).

Cassia VG et.al.,5 developed and validated a dissolution test for Rabeprazole sodium coated tablets using a reverse-phase liquid chromatographic method. The dissolution medium used were HCl 0.1M and borate buffer pH 9.0 for acidic and basic steps, respectively, volume of 900 ml for both. Suitable stirring speed for the study, paddle at 75 rotations per minute (rpm) was used. The quantitation method was also adapted and validated. Less than 10% of the labelled amount was released in the acid step, while more than 95% was achieved over 30 min in the basic one. The dissolution profile for tablets was considered satisfactory.

Ela H et.al.,6 developed and validated a method to assess the dissolution behavior of Rociverine sugar-coated tablets. They developed an HPLC–MS in reverse phase method of analysis for the dosage of unknown Rociverine solution. This analytical method was applied to determine the dissolution rate of Rociverine tablets produced by the industrial procedure, since there is no official method description. Dissolution tests were carried out in sink conditions, dissolution medium contained 0.01N HCl, paddle rotation speed of 50rpm and vessel volume 1000 ml. The method was demonstrated to be adequate for quality control of Rociverine tablets. Validation was inferred from specificity, linearity, precision, accuracy and robustness.

Michael DL et.al.,7 developed and validated a dissolution test for a once daily combination tablet containing 10 mg of Cetirizine dihydrochloride for immediate release and 240 mg of Pseudoephedrine hydrochloride for extended release according to current ICH and FDA guidelines. The dissolution method, which uses USP apparatus 2 with paddles rotating at 50 rpm, 1000 ml of deaerated water as the dissolution medium, and reverse-phase HPLC for quantitation, was demonstrated to be robust, discriminating, and transferable. These test conditions were selected after it was demonstrated that the cetirizine HCl portion of the tablet rapidly dissolved in aqueous media over the physiologically relevant pH range of 1.1–7.5, and that the extended-release profile of pseudoephedrine HCl was independent of dissolution condition.

Timothy JM et.al.,8 developed and validated a dissolution method for Warfarin sodium-aspirin combination tablets which utilizes USP Apparatus I (baskets) at 50 rpm with 900 ml of phosphate buffer (pH 6.8; 0.05 M) medium at 37°C. A reversed-phase liquid chromatographic method was also developed for the simultaneous determination of warfarin sodium, aspirin and salicylic acid on an octadecylsilica column using acetonitrile-tetrahydrofuran-glacial acetic acid-water (23:5:5:67,v/v/v/v) as the mobile phase with UV detection at 282 nm. Validation data were obtained which demonstrated that the dissolution methodology is accurate, precise, linear and rugged for the combination tablets.

Wood JA et.al.,9 developed a dissolution testing method for tablet formulation containing one sustained release and one fast release component required automation to allow periodic sampling over 24 h and high sample throughput. A Hewlett-Packard Multi-Bath Dissolution Testing System (MBDS), in conjunction with USP Apparatus II, was considered for this purpose, particularly because of its potential for high throughput with sustained release products. The MBDS can operate up to four dissolution apparatus simultaneously and generate a final report, including graphics, at the end of the run. However, the system can only be used with analytes with appropriate spectral properties because it operates with a diode-array spectrophotometer. The purpose of this work was determined applicability of multicomponent diode-array spectrophotometry to the formulation in question, and the extent to which the resulting procedure could be operated in compliance with GMP/GLP requirements for automated systems (21 CFR). Recently published clarifications of regulatory positions on this subject [l-3] were considered. The applicability of the methodology to the formulation was assessed from the quality of data, the ruggedness of the method and a comparison against an independent method. A protocol was devised to test and document the performance of the MBDS and dissolution apparatus. The protocol utilized all of the MBDS software driven diagnostics as well as a number of independent checks and documentation routines

Paraskevas DT et.al.,10 developed a dissolution test for Famotidine tablets which was optimized and validated using flow injection analysis (FIA). The effect of dissolution parameters such as pH, medium and stirring speed was studied, while the ruggedness of the procedure was validated. All measurements were performed using a simple direct spectrophotometric flow injection assay (λmax = 265 nm) that has also been optimized and fully validated in terms of linearity, limit of detection, precision, selectivity and accuracy. Linearity was obeyed in the range 50–150% of Famotidine (20–60 mg/L), while the detection limit (0.1 mg/L) and repeatability (sr < 1.0%, n = 12) were satisfactory. The sampling rate was 30/hr. The dissolution results during quality and stability control of two batches of Famotidine tablets obtained by the flow injection method were in good agreement with high-performance liquid chromatography (HPLC).

ENCLOSURE – III

6.3 Objective of the study

The present work is planned with the following objectives.

1. To develop and validate dissolution methods for few newer antiretroviral drugs.

2. To estimate antiretroviral drugs by UV and HPLC methods.

3. Statistical interpretation of the results.

ENCLOSURE – IV

7. MATERIALS AND METHODS

7.1 Source of data

The primary data will be collected by performing various tests and investigations in the laboratory.

The secondary data will be collected by referring various National and International journals, Books, Pharmacopeia’s, Helinet and Websites.

The day to day development in the area will be updated by literature survey through e-publishing, internet and current periodicals in our library and elsewhere.

All the basic facilities required for the estimation of antiretroviral drugs are available in our college laboratories.

ENCLOSURE – V

7.2 Method of collection of data

The data is planned to collect from laboratory experiments which includes,

1. Instruments like USP dissolution test apparatus, UV/visible Spectrophotometer, and HPLC instruments will be used to collect above data.

2. Advanced statistical software’s will be useds to interpret the collected data.

enclosure – VI

LIST OF REFERENCES

1. Siewert M, Dressman J, Brown C, Shah V, Williams R. FIP/AAPS guidelines for dissolution/in vitro release testing of novel/special dosage forms. Dissolution Technol 2003; 10:10-13,15.

2. Sílvia HM, Borgamann L, Lutiane P, Marcela ZA, Liziane B, Simone GC. Development and Validation of a Dissolution Method with Spectrophotometric Analysis for Diacerhein Capsules. Sci Pharm. 2008; 76: 541–554.

3. Sean SJ, Alex MO, Beverly N Hong J, Monica D, Mark B. Validation of a dissolution method with HPLC analysis for Lasofoxifene tartrate low dose tablets. Journal of Pharmaceutical and Biomedical Analysis. 2007; 44 :1064–1071.

4. Paraskevas DT, Aspasia V, Theodora B. Optimization and validation of a dissolution test for Famotidine tablets using flow injection analysis. Journal of Pharmaceutical and Biomedical Analysis. 2006; 41:437–441.

5. Cassia VG, Clesio SP, Martin S, Elfrides ESS. Development and validation of a dissolution test for Rabeprazole sodium in coated tablets. Journal of Pharmaceutical and Biomedical Analysis. 2006; 41:833–837.

6. Ela H, Roberta C, Massimo R, Ledjan M, Luciano B, Sante M, Maurizio V, Piera D M. Validation of an HPLC–MS method for Rociverine tablet dissolution analysis. Journal of Pharmaceutical and Biomedical Analysis. 2008; 47:422–428.

7. Michael DL, Hany LM, Jeffrey WH . Development and validation of a dissolution test for a once-a-day combination tablet of immediate-release satirizing dihydrochloride and extended-release pseudoephedrine hydrochloride. Journal of Pharmaceutical and Biomedical Analysis 2005; 39: 543–551.

8. Timothy JM, Alvin B. Gibson, Frank JD. Development and validation of a dissolution method for Warfarin sodium and Aspirin combination tablets. Journal of Pharmaceutical and Biomedical Analysis 1997 ;15:1881-1891.

9. Wood JA and Gqras JT. Validating an automated dissolution method for tablet containing both sustained and immediate release active components. Journal of pharmaceutical & Biomedical Analysis. 1993 ; 11:1361-1365.

10. Paraskevas DT, Aspasia V, Theodora B .Optimization and validation of a dissolution test for Famotidine tablets using flow injection analysis. Journal of Pharmaceutical and Biomedical Analysis 2006 ; 41: 437–441.

................
................

In order to avoid copyright disputes, this page is only a partial summary.

Google Online Preview   Download