(766e) Dissolution of Carbamazepine Crystallized Directly Onto Excipients

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>...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/...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).

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
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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.