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Excipients & Actives for Pharma No. 26, 2011 Based on these calculations, the apparent diffusion coefficient of the drug in the polymeric matrix could be determined: D = 1.7, 2.4 and 4.0 x 10 -7 cm²/s for 10, 20 and 40% initial drug content. Knowing these values, the resulting drug release kinetics can be predicted for arbi trary tablet dimensions. One example is shown in figure 5 (dotted curves). These theoretical predictions could successfully be confirmed by independent experiments (symbols in figure 5). Equation 1 M t M∞ = 1- 32 π² ·∑∞ n=1 Fick’s second law of diffusion 1 ·exp q² ( - n R c q² n ² ·D·t ) ·∑∞ p=0 1 (2·p+1) 2 ·exp ( - (2·p+1)2· π² H ² ·D·t ) Conclusion Diprophylline release from Kollidon ® SR tablets is primarily controlled by diffusion. The mathematical model presented allows for a facilitated optimization of this type of drug delivery system. Based on this mathematical approach, a drug release profile can be easily adapted to the specific therapeutic application by reducing the necessary experiments and hereby facilitating faster formulation development. REFERENCES [1] Siepmann, F; Eckart, K; Maschke, A; Kolter, K; Siepmann, J. Modeling drug release from PVAc/PVP matrix tablets. Journal of Controlled Release 141, 216-222, 2010. [2] J. Crank. The Mathematics of Diffusion. Clarendon Press, Oxford, 1975. Drug released [%] 100 75 50 25 0 FIGURE 4 40% diprophylline 20% 10% theory 0 6 12 18 24 Time [h] Experiment (symbols) and theory (curves): Diprophylline release from Kollidon SR tablets with different initial drug loadings in phosphate buffer pH 7.4. (diameter = 11.3 mm). Reprinted from reference [1], with permission Drug released [%] 100 75 50 25 0 FIGURE 5 theoretical prediction 1.3mm, experiment 3.9mm, experiment 0 6 12 18 24 Time [h] Theoretical prediction (dotted curves) and independent experimental verification (symbols): Effects of the tablet height on diprophylline release from Kollidon SR tablets in phosphate buffer pH 7.4 (drug loading: 20%, diameter = 11.3 mm). Reprinted from reference [1], with permission Page 10
Excipients & Actives for Pharma No. 26, 2011 STABILITY OF FORMULATED OXYGEN-SENSITIVE ACTIVE INGREDIENTS Extended stabilization of active ingredients highly sensitive to oxidation using Kollidon 30 LP Angelika Maschke, Karl Kolter INTRODUCTION | Pharmaceutical formulators regularly require a low peroxide content in the excipients used to avoid degradation of the active ingredients (APIs) used. BASF fulfils this need to the maximum extent with its high-quality Kollidon grades and the packaging concept introduced in this ExAct issue (see pages 2-4). Moreover, the formulation of drugs that are highly sensitive to oxidation has become an additional major challenge for formulation scientists. For this purpose, it is of the utmost importance to use excipients with an especially low peroxide content. Considering the close contact between active ingredients and excipients during wet granu lation or direct compression, the peroxide level of the excipient has a strong impact on the stability of the API. As a first formulation approach, the stability of the API in a binder solution allows the appropriate binder to be identified. The goal of this study was to investigate the effect of the peroxide content of povidone on API stability in solution. Using Kollidon 30 LP in the formulation of actives highly sensitive to oxidation can significantly improve drug stability. Set-up of experiments The effect of Kollidon 30 Low Peroxide in solution on stabilization against oxidation was investigated using ascorbic acid and hydrocortisone as model substances. Povidones of different peroxide content (see table 1) were used to prepare a 20% aqueous solution. Ascorbic acid was incorporated at a 0.1% level and hydrocortisone at 0.025%. For the stability study, the samples were filled in glass vials incubated with or without argon, closed with a rubber cap and sealed with a cramp. The solutions were stored for 3 months at 25°C and 60% relative humidity. The API content was determined by HPLC. Results Both drug substances showed higher stability in solutions prepared with Kollidon 30 LP. After 1 month in Kollidon 30 LP solution, the ascorbic acid content was 50% vs. 30% in a PVP solution with a starting peroxide level of < 260ppm (Figure 1). A similar stabilization effect was found for hydrocortisone solutions (Figure 2). Povidone Peroxide content Kollidon 30 LP Very low < 20 ppm PVP 30 Low < 260 ppm PVP 30 Enriched 370 ppm TABLE 1 Povidone grades used for preparing aqueous acid solutions Page 11
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