British Association For Crystal Growth Annual Conference 2017
Stepwise use of additives for improved control over formation and
stability of mefenamic acid nanocrystals
1
1
K. Bodnar, S. P. Hudson, Å. C. Rasmuson
1
1,2
Synthesis and Solid State Pharmaceutical Centre, Department of Chemical and Environmental Sciences,
Bernal Institute, University of Limerick, Ireland
2
Department of Chemical Engineering and Technology, KTH Royal Institute of Technology, Sweden
[email protected]
Many potential drug candidates have poor water solubility and slow dissolution rates in vivo, leading to
limited bioavailability and failure to reach the market [1]. Antisolvent precipitation is a potential low-energy
crystallization method for the industrial production of drug nanocrystals to overcome dissolution limited
bioavailability. Additives are generally used in the process to promote nucleation, inhibit crystal growth and
stabilize the system against subsequent particle transformation and are present in the solvent or antisolvent
phase prior the mixing of the two solutions [2,3]. However, the identification of suitable additives for a
particular drug is challenging due to the lack of fundamental understanding about the specific action of
different additives in the nanocrystal preparation process.
In the present study [4], a method of introducing additives at different times during the process, i.e.
stepwise addition of additives, has been developed to separately target nucleation and particle
growth/transformation processes and produce stable nanoparticles of mefenamic acid (MEF) by antisolvent
precipitation. In the absence of additives, under optimized conditions, MEF crystals were prepared in the size
range of 0.25 µm – 3.05 µm. However, these crystals formed large agglomerates in suspension (~12.1 µm).
The influence of various single additives on the particle size in suspension, and on the size, habit and
polymorphic form of the isolated particles was investigated to identify the particular action of each additive in
the nanocrystal formation and stabilization processes. Of the eight additives studied, an anionic surfactant,
docusate sodium (DOSS), was the most effective for the preparation of nanoparticles in suspension
(D[4,3]=312 nm). The presence of DOSS promoted nucleation of the particles resulting in a reduced sized of
the individual crystals and prevented particle agglomeration. However, a gradual increase in particle size in
suspension during aging was observed and was associated with a polymorphic transformation. In contrast,
the presence of hydroxypropyl methylcellulose (HPMC) and polyvinyl alcohol (PVA) interfered with the
formation of MEF particles resulting in larger particle sizes and reduced crystallinity compared to in their
absence. The presence of these polymers did not prevent particle agglomeration in suspension, but they did
prevent polymorphic transformation through inhibiting the nucleation and/or growth of the stable polymorph.
Based on the results with single additives, for the first time to our knowledge, stepwise addition of additive
combinations was used to separately target the nucleation and particle growth/phase transformation
processes. Combining the initial use of DOSS for nucleation control with subsequent addition of HPMC or
PVA (5 seconds later) for stabilization of the polymorphic form allowed for the preparation of a stable
suspension of MEF nanocrystals (Figure 1).
This study demonstrates that the influence of different additives on the different mechanisms involved in
the manufacturing of nanocrystal suspensions varies. Additives that have an adverse effect on the nucleation
of the nanoparticles can be useful for stabilization if added later in the process. Thus, appropriate timing for
the addition of each additive can exploit their favorable properties, allowing for a more targeted application of
the additives and greater control over the properties of the product nanocrystals during antisolvent
precipitation processes.
British Association For Crystal Growth Annual Conference 2017
D[4,3] (µm)
0.8
0.6
0.4
0.2
0.0
0
30
60
90
120
Aging time (min)
Fig. 1: Volume-weighed mean size, D[4,3], of MEF suspensions over time, prepared in the presence of () DOSS,
() DOSS and subsequent addition of HPMC at 5 s aging time, and () DOSS and subsequent addition of PVA
at 5 s aging time. [4]
References:
[1] M. S. Ku, W. Dulin, Pharm. Dev. Technol. 2012, 17, 285.
[2] S. Khan, M. de Matas, J. Zhang, J. Anwar, Cryst. Growth Des. 2013, 13, 2766.
[3] T. B. Tierney, Y. Guo, S. Beloshapkin, Å. C.Rasmuson, S. P. Hudson, Cryst. Growth Des. 2015, 15, 5213.
[4] K. Bodnár, S. P. Hudson, Å. C.Rasmuson Cryst. Growth Des. 2017, 17, 454