COMPARISON OF DISSOLUTION PROFILES: …

1 Docencia 507. COMPARISON OF DISSOLUTION PROFILES: current guidelines . , , Dpto. Farmacia y Tecnolog a Farmac utica, Facultad de Farmacia, Univ. Complutense de Madrid, Espa a. Introduction across the gastrointestinal tract. Because of the critical nature of the first two steps, in vitro COMPARISON of therapeutic performances of two DISSOLUTION may be relevant to the prediction of medicinal products cantaining the same active in vivo performance. substance is a critical means of assessing the possibility of alternative using between the The BCS can be used as a basis for setting in innovator and any essentially similar medicinal vitro DISSOLUTION specifications and can also product. Assuming that in the same subject an provide a basis for predicting the likelihood of essentially similar plasma concentration time achieving a successful in vivo-in vitro course will result in essentially similar correlation (IVIVC).

2 Based on drug solubility concentration at the site of action and thus in and permeability, the BCS is recommended: an essentially similar effect, pharmacokinetic (2): data instead of therapeutic results may be used - Case 1: High Solubility High to establish equivalence: bioequivalence. Permeability. A bioequivalence study is basically a - Case 2: Low Solubility High Permeability. comparative study designed to establish - Case 3: High Solubility Low Permeability. equivalence between test and reference - Case 4: Low Solubility Low Permeability. products. In vivo bioequivalence studies are The BCS suggests that for high solubility, high needed when there is a risk that possible permeability drugs and in some instances for differences in bioavailability may result in high solubility, low permability drugs, 85 %.

3 Therapeutic inequivalence. But it's also possible DISSOLUTION in N HCl in 15 minutes can to request a waiver of in vivo bioavailability ensure that the bioavailability of the drug is not and/or bioequivalence studies for solid oral limited by DISSOLUTION . In the case of low dosage forms based on an approach termed solubility / high permeability drugs, drug the Biopharmaceutics Classification System DISSOLUTION may be the rate limiting step for (BCS) (1). drug absorption and an IVIVC may be COMPARISON of DISSOLUTION profiles expected. A DISSOLUTION profile in multiple media is recommended for drugs products in this FDA guidelines : category. In the case of high solubility / low permeability drugs, permeability is the rate Drug absorption from a solid dosage form after controlling step and a limited IVIVC may be oral administration depends on the release of possible.

4 Drugs in case 4 present significant the drug substance from the drug product, the problems for oral drug delibery. DISSOLUTION or solubilization of the drug under physiological conditions, and the permeability 508 VI Congreso SEFIG y 3 as Jornadas TF. The DISSOLUTION profile COMPARISON may be EMEA guidelines : (4). carried out suing model independent or model dependent methods: (3) A simple model DISSOLUTION studies can serve several purposes independent approach uses a difference factor as, for example, to be used as a tool in quality (f1) and a similarity factor (f2) to compare control to demonstrate consistency in DISSOLUTION profiles. manufacture, to demonstrate similarity between reference products from different Member f1 = {[St=1n (Rt -T t)] / [St=1 n Rt]} * 100 States, to demonstrate similarity between different formulations of an ac tive substance f2 = 50 * log {[1+(1/n)St=1 n (Rt -T t)2] * 100} (variations and new, essentially similar products There is a specific procedure to determine included) and the reference medicinal product.

5 Difference and similarity factors as follows: If an active substance is considered highly 1. Determine the DISSOLUTION profile of two soluble, it is reasonable to expect that it will not products (12 units each) of the test and cause any bioavailability problems. A. reference products. bioequivalence study may in those situations be waived based on case history and similarity of 2. Using the mean DISSOLUTION values from DISSOLUTION profiles. The similarity should be both curves al each time interval, calculate justified by DISSOLUTION profiles, covering at least the difference factor (f1) and similarity three time points, using three different buffers. factor (f2) using the above equations. For curves to be considered similar, f1 values If an active substance is considered to have a should be close to 0, and f2 valuesshould low solubility and a high permeability, the rate be close to 100.

6 Generally, f1 values up to limiting step for absorption may be the dosage 15 (0-15) and f2 valuesgreater than 50 (50- form DISSOLUTION . In those cases a variety of test 100) ensure sameness or equivalence of conditions is recommended and adequate the two curves. sampling should be performed until 90 % of the This model independent method is most drug is dissolved or an asymptote is reached. suitable for DISSOLUTION profile COMPARISON Any methods to prove similarity if DISSOLUTION when three to four or more DISSOLUTION time profiles are accepted as long as they are points are available. The following justified. recommendations should alsom be considered: The similarity may be compared by model- - The DISSOLUTION measurements of the test independent or model-dependent methods and reference batches should be made by linear regression of the percentage under the same conditions.

7 The DISSOLUTION dissolved at specified time points, bu statistical time points for both the profiles should be COMPARISON of the parameters of the Weibull the same. The reference batch used function or by calculating a similarity factor as should be the most recently manufactured f2: prechange product. f2 = 50 * log {[1+(1/n)St=1 n (Rt -T t)2] * 100}. - Only one measurement should be considered after 85 % DISSOLUTION of both In this equation f2 is the similarity factor, n is teh the products. number of time points, R(t) is the mean percent - To allow use of mean data, the percent drug dissolved of a reference product, and coefficient of variation at the earlier time T(t) is the mean percent drug dissolved of points ( , 15 minutes) should not be a test product. The evaluation of similarity is more than 20 %, and at other time points based on the conditions of: should not be more than 10 %.

8 - A minimun of three time points (zero excluded). Docencia 509. - 12 individual values for every time points References for each formulation. - Not more than one mean value of > 85 % 1. Amidon, , H. Lennem s, Shah, dissiolved for each formulation. and Crison; A Theoretical Basis for a - That the standard desviation of the mean Biopharmaceutics Drug Classification: The of any product should be less than 10 % Correlation of In Vitro Drug Product from second to last time points. DISSOLUTION and In Vivo Bioavailability, Phamaceutical Research 12, 413-420, An f2 value between 50 and 100 suggests that 1995. the two DISSOLUTION profiles are similar. In cases where more than 85 % of the drug are 2. Guidance For Industry: Waiver of In Vivo dissolved within 15 minutes, DISSOLUTION profiles Bioavailability and Bioequivalence Stidies may be accepted as similar without further for Inmediate-Release Solid Oral Dosage mathematical evaluation.

9 Forms Based on a Biopharmaceutics Classification System. FDA, 2000. A new approach on the use of the similarity factor f2 3. Guidance for Industry: DISSOLUTION Testing of Inmediate Release Solid Oral Dosage In researchments carried out in our department Forms. FDA, 1997. (5), it has been demonstrated that similarity factor (f2) is a simple measure for the 4. Note for Guidance on the Investiagation of COMPARISON of two DISSOLUTION profiles, but 2f Bioavailability and Bioequivalence. EMEA. factor is a slanted and conservative estimator of London, 2001. similarity factor real value. The statistical distribution of the f2 metrics has been simulated 5. Prior A., Frutos P., Frutos G., Torrado using the Bootstrap method. A relatively robust Susana, Correa C.; Estudio Comparativo distribution and a statistical correction of the de los Medicamentos Integrantes del slant were obtained.

10 Grupo Homog neo Alopurinol 300 mg 30. comprimidos , V Spanish-Portuguese In conclusion, it is plain that the use of Conference on Controlled Drug Release, Bootstrap confidence intervals is an useful tool Abstract Book, 159-160, 2002. in order to simulate the confidence the confidence interval for similarity factor f2.