Candurin pearl effect colors: Excellent compatibility with different pharmaceutical film coatings

Transcription

1 Technical Information Candurin pearl effect colors: Excellent compatibility with different pharmaceutical film coatings Melanie Breidung, Ralf Schweinfurth Merck KGaA, Darmstadt Roberto Ognibene Merck Millipore, Darmstadt New studies on the use of Candurin pearl effect colors in pharmaceutical film coatings were conducted. According to the results, Candurin did not exhibit any negative influence on the coating functionality, such as disintegration time or controlled release. In addition to these findings, a protective function for a soluble colorant was noted when Candurin was used in top-coatings. Content General 1 Introduction 2 Part A: Influence on functionality 3 Part B: Light-protective function 6 Conclusion 7 References 8 Acknowledgement 8 Legal Disclaimer 8 Merck Millipore is a division of

2 Introduction In the pharmaceutical industry, film coatings are often used and well known to provide solid dosage forms with special functionalities and features. While originally the aim was to mask objectionable taste or odor of the active ingredients, over the course of time film coating technology has provided additional benefits including, e.g.: enhanced stability during production, packaging and transportation, easy swallowing, controlled release and disintegration. Even if the packaging is designed to protect sensitive active ingredients from extraneous influence such as light, this function can also be fulfilled by tablet coatings. Due to their good hiding power, solids in the form of pigments can be used to achieve effective light protection. Naturally, for functional coatings it is very important that such pigments added to the film coating formulation are inert and interfere with neither the functional polymers contained in coating nor with active ingredients in the tablet core. 1 The coloration of solid drugs is also a generally accepted and effective way to prevent medication errors and to increase the safety of drug use. In regard to this topic Guidance for Industry entitled Incorporation of Physical-Chemical Identifiers into Solid Oral Dosage Form Drug Products for Anticounterfeiting was presented by the U.S. Food and Drug Administration (FDA) in October With the aim of making it exceedingly difficult to create counterfeit medicines, the use of physical chemical identifiers (PCiDs), as for instance colorants and pigments, is described. These molecular markers may allow product authentication by their presence alone or may be used to code the product. 2 However, tablet film coatings are also applied to improve the visual appearance of pharmaceutical products. Candurin pearl effect colors a unique range of mineral food and pharmaceutical colors developed and manufactured by us play an important role here. These specific colors are based on a natural silicate (mica) combined with titanium dioxide and/or iron oxide. Candurin colors are easy to apply to coating systems and are widely used for applications in tablets and capsules. In the present study, the influence of Candurin pearl effect colors on the disintegration time and the release of tablet film coatings was evaluated (part A). The lightprotective function of Candurin in the film coating was examined in addition (part B). 2

3 Part A: Influence on functionality 1. Disintegration testing Application For all tests, placebos containing Parteck M 200 with 1.5 % Parteck LUB MST (Magnesium stearate) were used. Physical data for the placebos are shown in Fig. 1. Parteck is a product range of pharmaceutical excipients featuring specially designed particle qualities for solid dose formulations. The combination used provides rapid disintegration times as well as an excellent batch-to-batch consistency. The compatibility of Candurin with Parteck products was tested in an earlier study. It was shown that Candurin had no influence on compression behavior and dissolution time when directly compressed with Parteck excipients. 3 Coatings were performed with Candurin loadings of 0 % up to 44 % pigment based on dry polymer amount for both polymer types: hydroxypropyl methyl cellulose (HPMC) and amino methacrylate copolymer (EUDRAGIT E PO) (see Fig. 2). The transparent film coating solution was prepared using a Silverson Homogenizer LF 4T. Afterwards Candurin Silver Lustre was added while using a propeller stirrer. Tablets were coated with an O Hara Labcoat equipped with a spray gun Schlick 970/7-1 S75. All coatings were applied within the general recommended process parameters. In order to study the disintegration behavior according to USP, the equipment used was a PTZ Auto 4 EZ (basket-rack assembly). 4 HPMC is a water-soluble polymer and forms immediate release coatings. Therefore all tests were performed in 800 ml deionised water only. EUDRAGIT E PO is a cationic polymer which is soluble in gastric fluid up to ph 5.5. Due to its characteristics, all disintegration tests were performed in 800 ml 0.1 N HCl. After initial disintegration testing, all samples were stored under accelerated conditions of 40 C and 75 % relative humidity up to six months. For stability samples disintegration testing was carried out after 1 month, 3 months and 6 months under the same conditions as the initial tests. Figure 1 Physical data for placebo uncoated (RSD = relative standard deviation; disintegration testing in 800 ml deionised water) Placebo uncoated Placebo uncoated Thickness [mm] Diameter [mm] / Shape Weight [mg] 3.3 mm 7.0 mm / biconvex mg RSD: 0.64% 161 7kN compression force Hardness [N] Friability [%] Disintegration [sec] RSD: 7.88% 0.12% 128 sec ( sec) Figure 2 Abstract of formulations Applied polymer [mg/cm 2 ] HPMC / EUDRAGIT E PO Candurin Silver Lustre [% on polymer] Total applied solids [mg/cm 2 ] HPMC / EUDRAGIT E PO 1.5/ / / /2.2 3

4 Figure 3 HPMC coating containing 22% Candurin on polymer Figure 4 EUDRAGIT E PO coating containing 22% Candurin on polymer Figure 5 Results on initial disintegration testing HPMC (sample size n = 6) Disintegration medium: deionised water (800 ml) Disintegration time [sec] Placebo uncoated 2. HPMC 0% Candurin 3. HPMC 11% Candurin 4. HPMC 22% Candurin 5. HPMC 44% Candurin Figure 6 Statistical evaluation (initial disintegration testing HPMC) Placebo uncoated HPMC 0% HPMC 11% HPMC 22% HPMC 44% Average 166 sec 207 sec 211 sec 233 sec 270 sec Relative standard deviation 25.69% 13.40% 7.02% 4.64% 8.14% Results 4 All formulations with Candurin, even with the lowest concentration of 11 % relative to the polymer amount, resulted in a shiny and glossy surface which is characteristic for the use of pearl effect pigments. SEM pictures (Fig. 3 and Fig. 4) showed for the used polymers HPMC and EUDRAGIT E PO good and complete film formation. No inclusions or holes could be detected. Candurin platelets were observable and incorporated homogeneously in the film-building polymers. With regard to the HPMC-based coating system, the results did not show any unexpected effects on disintegration time (see Fig. 5). Up to the highest pigment loading of 44% Candurin Silver Lustre, the measured times were within the normal range. A tendency toward longer disintegration times in relation to increasing Candurin amounts can be caused by the increased amount of solids added to the film coating. By adding more Candurin, tablets became heavier; the film got thicker and harder. This may lead to longer disintegration times. As can be seen in Fig. 6, the statistical evaluation also showed differences in the spread of measured disintegration times. Especially tablet samples with low and medium Candurin concentrations featured very stable test results and small standard variances. However, compared to the uncoated placebos all samples containing Candurin in the coating led to results with minor deviations from average. During stability testing, all samples showed normal increases in disintegration over time (Fig. 7). The measured changes were in relation to the increase of the uncoated placebo as well as to the transparent HPMC coating (0 % Candurin ).

5 A very minor increase between initial disintegration testing and testing after 6 months was exhibited for the uncoated placebo (91 sec) as well as for the HPMC-coated tablets with 44 % Candurin (69 sec). This could lead to the expectation that higher Candurin concentrations stabilize the coating over the stability testing period. In any case, all samples containing Candurin in the coating showed a smaller increase, less than 100 seconds, compared to an HPMC coating without Candurin (176 sec). To clarify this observation, a more comprehensive study on this topic would be necessary. Tablets with EUDRAGIT E PO coating showed very fast disintegration in HCl independent from the added Candurin amounts. Disintegration testing after storage for 1, 3 and 6 months under accelerated conditions did not lead to unexpected results (results for stability testing EUDRAGIT E PO not shown). As for HPMC, disintegration time increased over the time, but no influence linked to the presence of Candurin could be identified. Similar positive results were also achieved for EUDRAGIT E PO ReadyMix, a new ready-to-use coating formulation based on the EUDRAGIT E PO polymer (results not shown). Besides the promising results for the water-soluble polymer HPMC, very good results for the tested polymer EUDRAGIT E PO were obtained as well (see Fig. 8). The results did not show any detectable effects of Candurin on the disintegration time. Due to the high pigmentbinding capacity of EUDRAGIT E PO the increasing Candurin amounts did not influence the measured times. Figure 7 Stability testing HPMC (sample size n = 6) Disintegration medium: deionised water (800 ml) Disintegration time [sec] Placebo uncoated 2. HPMC 0% Candurin 3. HPMC 11% Candurin 4. HPMC 22% Candurin 5. HPMC 44% Candurin Initial measurements Stability testing 1 month Stability testing 3 months Stability testing 6 months Figure 8 Results on initial disintegration testing EUDRAGIT E PO (sample size n = 6) Disintegration medium: 0.1 N HCl (800 ml) Disintegration time [sec] Placebo uncoated (average 189 sec) 2. EUDRAGIT E PO 0% Candurin (average 216 sec) 3. EUDRAGIT E PO 11% Candurin (average 241 sec) 4. EUDRAGIT E PO 22% Candurin (average 238 sec) 5. EUDRAGIT E PO 44% Candurin (average 190 sec) 5

6 2. Enteric coating Application To examine the influence of Candurin in the coating on the release of active ingredients, tablets containing quinidine sulfate were used for this study. EUDRAGIT L30 D-55, an anionic polymer with methacrylic acid as a functional group, was applied to achieve an effective and stable enteric coating on these tablets. All tablets were coated with an O Hara Labcoat equipped with a spray gun Schlick 970/7 1 S75. The amount of polymer applied was 6 mg / cm 2, the concentration of Candurin Orange Amber was 10 % relative to the dry polymer amount. To study the release behavior according to the USP method, a Paddle apparatus (USP Apparatus 2) was used. Tablets were placed for 2 hours in 900 ml 0.1N HCl before phosphate buffer (changed to ph 6.8) was dosed to the medium. 5 Results As specified by USP, the measured results showed a release lower than 10 % in 0.1 N HCl within the first 120 minutes (see Fig. 9). By adding phosphate buffer to the medium, leading to a controlled increase in the ph, the release process started. After additional 30 minutes, almost 75 % of the active ingredient quinidine sulfate was released. Figure 9 Release performance of EUDRAGIT L30 D-55 coating containing Candurin (sample size n = 3) Release [%] Buffer ph 6.8 Procedure: USP Apparatus 2, 2h 0.1 N HCl, 900 ml, afterwards phosphate buffer (to ph 6.8), 50 rpm Part B: Light-protective function The influence of Candurin on the photostability of other colors within the coating was studied. The application of Candurin in combination with an additional blue colorant in a one-step coating was compared to a Candurin top-coating on a previously applied blue color coating. Application Samples A: color + Candurin within same coating Sample A1: Blind sample Coated tablets with dye FD&C Blue #2 (E132) (without Candurin Silver Sheen) weight gain in dry matter: 1.0 % Sample A2: Comparison sample Coated tablets with dye FD&C Blue #2 (E132) and Candurin Silver Sheen weight gain in dry matter: 1.8 % Samples B: color coating + Candurin top-coating Sample B1: Blind sample Color coated tablets with dye FD&C Blue #2 (E132) and top-coating without Candurin Silver Sheen weight gain in dry matter: 1.0 % Sample B2: Comparison sample Color coated tablets with dye FD&C Blue #2 (E132) and top-coating with Candurin Silver Sheen weight gain in dry matter: 1.8 % 6

7 All samples were prepared using an HPMC based film coating solution. The study was conducted according to ICH Guideline 1B Photostability Testing of New Active Substances and Medicinal Products. According to the guideline the light stressing was carried out for 24 hours using a Heraeus Suntester Xenon lamp (ID65 / 1.2Mio.Lxh / 250W/m 2 ). Dark controls wrapped in aluminum foil were placed alongside the LUMI samples. 6 In order to evaluate the influence of light exposure based on l*a*b* color space, a Minolta CR 300 (measurement geometry d/0 ) was used. Instrumental color differences Delta E < 1.5 was defined as low. 7 Result Requirement Delta E < 1.5 was not fulfilled for Samples A1 + A2: color and Candurin within same coating; nor for Sample B1, where the blue color coating was covered by a transparent top-coating. The visual assessment as well as the statistical evaluation of illuminated tablets versus non-illuminated tablets showed differences for these mentioned samples. Figure 10 Boxplot: statistical evaluation of Sample B2 Delta L / a / b = dark sample (non-illuminated) Delta L_1 / a_1 / b_1 = LUMI-sample (illuminated) Dark sample LUMI-sample Sample B2: color coating + Candurin top-coating fulfilled the requirement Delta E < 1.5. According to the statistical evaluation based on photostability testing performed (Fig. 10), the specification Light exposure does not result in unacceptable color change was achieved. Regarding these results it can be assumed that Candurin within top-coatings might provide a light-protective function for colorants in the previously applied color coating. The achieved results can also lead to the expectation that tablet coatings containing Candurin could provide light protection for active ingredients in the tablet, being sensitive to light influences. However, to clarify this theory a comprehensive study on that topic would be essential. Conclusion The present study demonstrates the very good compatibility of Candurin pearl effect colors with different film coating polymers. No negative influences were observed: neither on disintegration time nor the release of active ingredient contained in the tablet. Furthermore, a certain light protecting function for an instable colorant was detected when Candurin was used in a top coating. The results show the safe and effective use of Candurin in pharmaceutical film coatings. The distinctive pearl effect on oral dosage forms can support anticounterfeiting and help to prevent medication errors. 7

8 References 1. W. A. Ritschel, A. Bauer-Brandl, Die Tablette - Handbuch der Entwicklung, Herstellung und Qualitätssicherung, Editio Cantor Verlag Aulendorf Federal Register, Vol. 76, No. 197, / October 12, A. von der Brelie, R. Ognibene, L. Ohrem, Candurin and Parteck : Fast dissolution for hard and unmistakable tablets, Merck KGaA USP 35 NF 30, < 701> Disintegration 5. USP 35 NF 30, <724> Controlled Release 6. European Medicines Agency, ICH Topic Q1B Photostability Testing of New Active Substances and Medicinal Products (CPMP/ICH/279/95), January H. Loos, Farbmessung, Verlag Beruf und Schule, 1989 Acknowledgement We thank Evonik Industries AG, Darmstadt for their cooperation. Legal Disclaimer The typical technical data above serve to generally characterize the excipient. These values are not meant as specifications and they do not have binding character. The product specification is available separately, from the website: We provide information on application technologies and relevant regulations based upon our current knowledge and opinion at the time of printing. We make no representation or warranty of any kind, express or implied, including merchantability or fitness for a particular use, with respect to such information or its application. Purchasers must independently determine the suitability of our ingredients for the purchaser s intended product, use or process. Purchaser is responsible for observing all laws and regulations relevant to such products, uses or processes. The fore going information and suggestions are also provided without warranty of non-infringement as to the intellectual property rights of third parties, and shall not be construed as any inducement to infringe the rights of third parties. For more information and documentation please contact: Phone: candurin@merckgroup.com Merck KGaA Frankfurter Straße Darmstadt Germany Merck Millipore, the M logo, Candurin and Parteck are trademarks of Merck KGaA, Darmstadt, Germany. EUDRAGIT is a registered trademark of Evonik Röhm GmbH, Darmstadt, Germany Merck KGaA, Darmstadt, Germany. All rights reserved.