Understanding How Polymeric Additives Can Inhibit Crystallization

 

This work is provided by Dr. Kaoutar Abbou Oucherif, who holds a doctorate in Chemical Engineering from Purdue University. Her expertise is in developing both in vitro precipitation methods as well as oral absorption in silico tools to further understand the precipitation behavior of pharmaceutical compounds and their impact on bioavailability. 

Over the last decade there has been a continuing increase in the number of poorly soluble compounds in the pharmaceutical pipeline. Poor solubility brings many challenges to the successful delivery and commercialization of drugs as it can lead to a decrease in gastrointestinal absorption and hence bioavailability. One of the strategies to improve solubility in vivo is the use of amorphous compounds. The latter, however, are at a higher energy state than their crystalline counterparts and hence it is of paramount importance to prevent the crystallization of the amorphous form both at the solid (during storage) and aqueous states (upon dissolution in vivo).

To prevent crystallization, amorphous drugs are often combined with a carrier polymer to form an amorphous solid dispersion. Therefore, understanding the mechanisms by which these polymeric additives can inhibit crystallization can help with formulation strategies. In this work, the nucleation behavior of supersaturated APAP solutions was studied in the presence and absence of cellulosic and vinyl polymers-- PVP, PVPVA, HPMC, HPMCAS, and PAA-- using turbidimetry and particle count and image analysis techniques. The nucleation rates in the presence of the different polymers were obtained from the cumulative distribution function of induction times. The onset of nucleation was determined based on changes in solution turbidity measured with the Crystal16.

 

 

Micrographs of APAP crystallized from buffer (a) and solutions of HPMCAS (b), PAA (c), PVP (d), PVPVA (e) and HPMC (f). The scale bar represents 500µm.

 

 

While nucleation rates can be estimated from induction times, these rates are only measured at the initial supersaturation at which nucleation takes place. To obtain nucleation rates as the system continues to precipitate, experiments were performed using the CrystallinePV particle viewer camera setup. Image analysis was  conducted on the captured images of APAP during precipitation to obtain the number of counts of APAP crystals as a function of time. The change in the number of counts of crystals as a function of time is directly proportional to the nucleation rate and was then used to compare the relative impact of each polymer on both the primary and secondary nucleation kinetics of APAP.

Using image analysis can provide more information regarding the effect of polymers on the nucleation behavior of drugs from supersaturated solutions than by simply considering induction times. In this case, the Crystal16 system is useful in elucidating the primary nucleation kinetics while the CrystallinePV system allows one to determine both the primary and secondary nucleation kinetics. This was best shown in the case of vinyl polymers where based solely on the very long nucleation induction times of PVP and PVPVA, it could be included that they have similar primary nucleation inhibition behavior. However, when nucleation kinetics were determined using image analysis, PVPVA was not nearly as effective as PVP and was less effective than the cellulosic polymers. The onset of nucleation was greatly retarded in the presence of PVPVA; however, once nucleation occurred, the number of APAP particles formed increased quickly. Therefore it seems that PVPVA may be good at inhibiting primary nucleation but does not appear to be very effective at preventing or decreasing the rate of secondary nucleation. Overall PVP and the cellulosic polymers were found to be the most effective at nucleation inhibition at the supersaturations studied. The order of efficacy of the polymers was found to be different from that observed for crystallization inhibition in amorphous acetaminophen indicating that there are different factors at play in an aqueous environment.

 
Niraj S. Trasi, Kaoutar Abbou Oucherif, James D. Litster and Lynne S. Taylor, Evaluating the influence of polymers on nucleation and growth in supersaturated solutions of acetaminophen, CrystEngComm, 2015, 17, 1242-1248.