Enhancement of the Physical Stability of Amorphous Sildenafil in a Binary Mixture, with either a Plasticizing or Antiplasticizing Compound

Abstract

The main purpose of this paper was to evaluate the impact of both high- and low-Tg polymer additives on the physical stability of an amorphous drug, sildenafil (SIL). The molecular mobility of neat amorphous SIL was strongly affected by the polymeric excipients used (Kollidon VA64 (KVA) and poly(vinylacetate) (PVAc)). The addition of KVA slowed down the molecular dynamics of amorphous SIL (antiplasticizing effect), however, the addition of PVAc accelerated the molecular motions of the neat drug (plasticizing effect). Therefore, in order to properly assess the effect of the polymer on the physical stability of SIL, the amorphous samples at both: isothermal (at constant temperature—353 K) and isochronal (at constant relaxation time—τα = 1.5 ms) conditions were compared. Our studies showed that KVA suppressed the recrystallization of amorphous SIL more efficiently than PVAc. KVA improved the physical stability of the amorphous drug, regardless of the chosen concentration. On the other hand, in the case of PVAc, a low polymer content (i.e., 25 wt.%) destabilized amorphous SIL, when stored at 353 K. Nevertheless, at high concentrations of this excipient (i.e., 75 wt.%), its effect on the amorphous pharmaceutical seemed to be the opposite. Therefore, above a certain concentration, the PVAc presence no longer accelerates the SIL recrystallization process, but inhibits it.

High-Pressure Dielectric Studies—a Way to Experimentally Determine the Solubility of a Drug in the Polymer Matrix at Low Temperatures

“…A similar behavior was also observed during the recrystallization of flutamide in the flutamide–Kollidon VA64 system, 37 aripiprazole in compositions with Kollidon VA64 or Soluplus, 41 and sildenafil in the sildenafil + Kollidon VA64 ASD system. 43 It is worth mentioning that the opposite phenomenon, the shift of the α-relaxation process toward higher frequencies during the recrystallization corresponding to the enhancement of the plasticizing effect, can be observed in the systems based on a high- T g API and a low- T g polymer such as sildenafil + poly vinylacetate. 43 When the recrystallization of the excess amount of NMS from the supersaturated solution had ceased, one loss peak could be observed in the dielectric loss spectrum (see panels (a,b) of Figure 5 ).…”

“…43 It is worth mentioning that the opposite phenomenon, the shift of the α-relaxation process toward higher frequencies during the recrystallization corresponding to the enhancement of the plasticizing effect, can be observed in the systems based on a high-T g API and a low-T g polymer such as sildenafil + poly vinylacetate. 43 When the recrystallization of the excess amount of NMS from the supersaturated solution had ceased, one loss peak could be observed in the dielectric loss spectrum (see panels (a,b) of Figure 5). Next, we performed additional experiments, in which the sample after recrystallization was remeasured during heating to determine the molecular dynamics of the system in a broad temperature range [see panels (c,d) of Figure 5].…”

“…BDS is an experimental technique already applied to determine the solubility limit at ambient pressure. 39 − 43 Moreover, due to the fact that this method has been repeatedly used to test amorphous materials under elevated pressures, 32 , 44 in particular, as it has been recently shown to determine the aforementioned solubility under elevated pressure conditions, 37 , 38 we chose it as the main experimental technique.…”

Sildenafil 4.0—Integrated Synthetic Chemistry, Formulation and Analytical Strategies Effecting Immense Therapeutic and Societal Impact in the Fourth Industrial Era

“…According to the BCS nomenclature and the regulatory biowaiver guidelines, sildenafil citrate is classified as an active pharmaceutical ingredient (API) of low solubility and high membrane permeability, even though it meets the criteria of highly soluble API at pH 4 environments [ 13 ]. Enhancement of amorphous sildenafil’s physical stability has been evaluated by investigating the impact of Tg polymer additives [ 14 ].…”

Amorphous Form of Carvedilol Phosphate—The Case of Divergent Properties

“…The resulting disadvantages are attributed to forming a hard film on the API surface, reducing solvent penetration, thereby drastically reducing solubility. An essential aspect of the development of formulations containing amorphous forms is the proper selection of excipients, ensuring the stability of the amorphous form by creating a spatial hindrance limiting the mobility of API molecules [ 19 , 20 , 21 ]. Selected polymers can also provide a protective form, limiting the access of water molecules starting the recrystallization process [ 22 , 23 , 24 ].…”