467777 Dissolution of Carbamazepine Crystallized Directly Onto Excipients

Friday, November 18, 2016: 9:38 AM
Continental 5 (Hilton San Francisco Union Square)
Vivek Verma1, Clare M. Crowley1, Peter Davern1, Sarah Hudson1 and B. Kieran Hodnett2, (1)Synthesis & Solid State Pharmaceutical Centre, Chemical and Environmental Sciences, University of Limerick, Limerick, Ireland, (2)Synthesis & Solid State Pharmaceutical Centre, Science & Engineering Faculty, University of Limerick, Limerick, Ireland

Dissolution of Carbamazepine Crystallized Directly onto Excipients

Vivek Verma, Clare M Crowley, Peter Davern, Sarah Hudson & B. Kieran Hodnett

Synthesis and Solid State Pharmaceutical Centre, Department of Chemical and Environmental Sciences, Materials and Surface Science Institute,University of Limerick, Ireland

Email ID: vivek.verma@ul.ie

For BCS Class II drugs, such as carbamazepine (CBMZ), in vivo bioavailability is significantly affected by dissolution rate  ADDIN EN.CITE <EndNote><Cite><Author>Lindenberg</Author><Year>2004</Year><RecNum>339</RecNum><DisplayText>[1]</DisplayText><record><rec-number>339</rec-number><foreign-keys><key app="EN" db-id="zvp25de0dx0w06exsw9prrv5rvvszxv5zr2x">339</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Lindenberg, Marc</author><author>Kopp, Sabine</author><author>Dressman, Jennifer B.</author></authors></contributors><titles><title>Classification of orally administered drugs on the World Health Organization Model list of Essential Medicines according to the biopharmaceutics classification system</title><secondary-title>European Journal of Pharmaceutics and Biopharmaceutics</secondary-title></titles><periodical><full-title>European Journal of Pharmaceutics and Biopharmaceutics</full-title></periodical><pages>265-278</pages><volume>58</volume><number>2</number><keywords><keyword>Biopharmaceutical classification system</keyword><keyword>Permeability</keyword><keyword>Solubility</keyword><keyword>Absorption</keyword><keyword>World Health Organization</keyword><keyword>Essential Medicines</keyword></keywords><dates><year>2004</year><pub-dates><date>9//</date></pub-dates></dates><isbn>0939-6411</isbn><urls><related-urls><url>http://www.sciencedirect.com/science/article/pii/S0939641104000438</url></related-urls></urls><electronic-resource-num>http://dx.doi.org/10.1016/j.ejpb.2004.03.001</electronic-resource-num></record></Cite></EndNote>[1]. Conventional approaches to improving dissolution rates have relied on mechanical particle size reduction techniques (e.g., attrition, impact or shearing) but these approaches can lead to degradation of active pharmaceutical ingredients (APIs), non-uniform crystal size distributions and the incorporation of impurities  ADDIN EN.CITE <EndNote><Cite><Author>Horn</Author><Year>2001</Year><RecNum>329</RecNum><DisplayText>[2]</DisplayText><record><rec-number>329</rec-number><foreign-keys><key app="EN" db-id="zvp25de0dx0w06exsw9prrv5rvvszxv5zr2x">329</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Horn, Dieter</author><author>Rieger, Jens</author></authors></contributors><titles><title>Organic Nanoparticles in the Aqueous Phase—Theory, Experiment, and Use</title><secondary-title>Angewandte Chemie International Edition</secondary-title></titles><periodical><full-title>Angewandte Chemie International Edition</full-title></periodical><pages>4330-4361</pages><volume>40</volume><number>23</number><keywords><keyword>carotenoids</keyword><keyword>disperse systems</keyword><keyword>nanoparticles</keyword><keyword>nanostructures</keyword><keyword>phase transformations</keyword></keywords><dates><year>2001</year></dates><publisher>WILEY-VCH Verlag GmbH</publisher><isbn>1521-3773</isbn><urls><related-urls><url>http://dx.doi.org/10.1002/1521-3773(20011203)40:23&lt;4330::AID-ANIE4330&gt;3.0.CO;2-W</url><url>http://onlinelibrary.wiley.com/store/10.1002/1521-3773(20011203)40:23&lt;4330::AID-ANIE4330&gt;3.0.CO;2-W/asset/4330_ftp.pdf?v=1&amp;t=ilm44kjl&amp;s=bf5c1a75e7a80f8be75b3afa39f65a1725d7371f</url></related-urls></urls><electronic-resource-num>10.1002/1521-3773(20011203)40:23&lt;4330::AID-ANIE4330&gt;3.0.CO;2-W</electronic-resource-num></record></Cite></EndNote>[2]. To overcome these problems the pharmaceutical industry is currently focussing on a variety of ‘bottom-up’ approaches (e.g., spray drying,  antisolvent precipitation, sonoprecipitation, etc.) to reduce the crystal size distributions  ADDIN EN.CITE <EndNote><Cite><Author>Poornachary</Author><Year>2016</Year><RecNum>313</RecNum><DisplayText>[3]</DisplayText><record><rec-number>313</rec-number><foreign-keys><key app="EN" db-id="zvp25de0dx0w06exsw9prrv5rvvszxv5zr2x">313</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Poornachary, Sendhil K.</author><author>Han, Guangjun</author><author>Kwek, Jin Wang</author><author>Chow, Pui Shan</author><author>Tan, Reginald B. H.</author></authors></contributors><titles><title>Crystallizing Micronized Particles of a Poorly Water-Soluble Active Pharmaceutical Ingredient: Nucleation Enhancement by Polymeric Additives</title><secondary-title>Crystal Growth &amp; Design</secondary-title></titles><periodical><full-title>Crystal Growth &amp; Design</full-title></periodical><pages>749-758</pages><volume>16</volume><number>2</number><dates><year>2016</year><pub-dates><date>2016/02/03</date></pub-dates></dates><publisher>American Chemical Society</publisher><isbn>1528-7483</isbn><urls><related-urls><url>http://dx.doi.org/10.1021/acs.cgd.5b01343</url><url>http://pubs.acs.org/doi/pdfplus/10.1021/acs.cgd.5b01343</url></related-urls></urls><electronic-resource-num>10.1021/acs.cgd.5b01343</electronic-resource-num></record></Cite></EndNote>[3].

In this study, the influence of dispersed excipient particles present during the batch crystallisation of metastable carbamazepine-methanol solutions has been examined. The rationale of this approach is that primary heterogeneous nucleation frequently reduces the free energy barrier to nucleation enabling nucleation to occur at lower supersaturations; increasing nucleation rates tends to reduces crystal size, potentially obviating the need to mill API batches.

CBMZ, a well known anti-epilectic drug and used in the treatment of neuralgia, was selected as the model API. Cooling crystallisations of CBMZ at supersaturations (S) of 1.22, 1.34 and 1.55, in the presence of dispersed excipient particles (α/β-Lactose (α/β-Lac), β-D-Mannitol (β-D-Man), microcrystalline cellulose (MCC) and carboxymethyl cellulose (CMC)), results in the production of CBMZ FIII crystals. The presence of CBMZ FIII crystals was confirmed by PXRD and in situ SEM-Raman. Crystal size distribution (CSD) (Table 1) from SEM micrographs indicated a variation in CBMZ FIII crystal size of 5 – 50 μm (Figure 1). Interfacial interactions between the CBMZ FIII crystals and excipients particles was confirmed by in situ SEM-Raman. Dissolution rate of CBMZ FIII from the powder mixtures was enhanced with 70 – 82 % dissolution occurring within 15 mins compared with 42 % for CBMZ recrystallised in the absence of excipients under the same conditions (Figure 2).

Figure 2: % - Dissolution of CBMZ FIII crystallised in presence of excipients in PBS at pH = 7.4; sink conditions (40 mg/L); 3 hr aged samples; S = 1.22

Text Box: Figure 2: % - Dissolution of CBMZ FIII crystallised in presence of excipients in PBS at pH = 7.4; sink conditions (40 mg/L); 3 hr aged samples; S = 1.22

Table 1: Crystal size distribution (CSD) (D50 in μm) of CBMZ FIII crystals in presence and absence of excipients

S

Excipients

No Excipient

α/β-Lac

β-D-Man

MCC

CMC

1.22

16±11

13±14

17±11

13±7

22±10

1.34

23±14

13±7

14±7

32±22

12±4

1.55

17±9

18±10

19±10

20±10

27±12

Text Box: Table 1: Crystal size distribution (CSD) (D50 in μm) of CBMZ FIII crystals in presence and absence of excipients
S	Excipients	No Excipient	α/β-Lac	β-D-Man	MCC	CMC
1.22	16±11	13±14	17±11	13±7	22±10
1.34	23±14	13±7	14±7	32±22	12±4
1.55	17±9	18±10	19±10	20±10	27±12

Figure 1: CBMZ FIII CSD crystallised in presence of excipients along with their respective SEM micrographs; 3 hr aged samples; S = 1.22

Text Box: Figure 1: CBMZ FIII CSD crystallised in presence of excipients along with their respective SEM micrographs; 3 hr aged samples; S = 1.22        

Acknowledgements

This work was funded by Science Foundation Ireland under Grant 12/RC/2275.

References

 ADDIN EN.REFLIST 1.             Lindenberg, M., S. Kopp, and J.B. Dressman, European Journal of Pharmaceutics and Biopharmaceutics, 2004. 58(2): p. 265-278.

2.             Horn, D. and J. Rieger, Angewandte Chemie International Edition, 2001. 40(23): p. 4330-4361.

3.             Poornachary, S.K., et al., Crystal Growth & Design, 2016. 16(2): p. 749-758.


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