Co-Amorphous Simvastatin-Nifedipine with Enhanced Solubility for Possible Use in Combination Therapy of Hypertension and Hypercholesterolemia

Abstract

The high index of simultaneous incidence of hypertension and hypercholesterolemia in the population of many countries demands the preparation of more efficient drugs. Therefore, there is a significant area of opportunity to provide as many alternatives as possible to treat these illnesses. Taking advantage of the solubility enhancement that can be achieved when an active pharmaceutical ingredient (API) is obtained and stabilized in its amorphous state, in the present work, new drug-drug co-amorphous formulations (Simvastatin SIM- Nifedipine NIF) with enhanced solubility and stability were prepared and characterized. Results show that the co-amorphous system (molar ratio 1:1) is more soluble than the pure commercial APIs studied separately. Aqueous dissolution profiles showed increments of solubility of 3.7 and 1.7 times for SIM and NIF, correspondingly, in the co-amorphous system. The new co-amorphous formulations, monitored in time, (molar fractions 0.3, 0.5 and 0.7 of SIM) remained stable in the amorphous state for more than one year when stored at room temperature and did not show any signs of crystallization when re-heating. Inspection on the remainder of a sample after six hours of dissolution showed no recrystallization, confirming the stability of co-amorphous system. The enhanced solubility of the co-amorphous formulations makes them promising for simultaneously targeting of hypertension and hypercholesterolemia through combination therapy.

Keywords: Nifedipine; Simvastatin; amorphous drug; co-amorphous; hypercholesterolemia; hypertension; solubility.

Figure 1

Chemical structures of active pharmaceutical ingredients (a) Simvastatin SIM (cholesterol lowering agent) and (b) Nifedipine NIF (calcium channel blocker used to treat hypertension).

Figure 2

Thermograms for SIM, NIF, and representative binary mixtures (a) First heating of samples in crystalline phase. (b) Second heating of samples in amorphous form. (c) Glass transition temperatures of the amorphous samples freshly prepared and after one year of storage. Thermograms were obtained by diffential scanning calorimetry, DSC using a heating rate of 10 ${}^{\circ }$C/min. Molar fractions are in terms of SIM.

Figure 3

Phase transition diagram for the binary system SIM-NIF. Liquidus and eutectic temperatures shown in filled circles. In the phase diagram are also included the glass transition temperatures measured immediately after the quenching (empty circles) and after storage (empty squares).

Figure 4

Powder X-ray diffraction pattern for samples in crystalline form and samples in amorphous form studied as a function of storage time, measured by X-ray diffraction (XRD). (a) Pure SIM (b) SIM-NIF 1:1 (c) Pure NIF. (d) SIM-NIF 1:2 (e) SIM-NIF 2:1 Also, the XRD pattern of a remainder of a sample subjected to a dissolution process is shown in (b).

Figure 5

Aqueous dissolution profiles for pure crystalline APIs (SIMc and NIFc) and co-amorphous formulation SIM-NIF: (a) solubility for SIM (b) solubility for NIF.

Figure 6

Dissolution profiles in USP Phosphate Buffer pH 6.8 for pure crystalline APIs (SIMc and NIFc) and co-amorphous formulation SIM-NIF: (a) solubility for SIM (b) solubility for NIF.

Figure 7

Comparison of maximum solubility values of pure APIs in their crystalline form (SIMc and NIFc) and co-amorphous formulation (SIM-NIF). Maximum solubility values shown were obtained in two different media: deionized water and a controlled pH medium using USP phosphate buffer (pH = 6.8).

Figure 8

FTIR spectra of crystalline (c) and amorphous (a): SIM, NIF, and co-amorphous formulation SIM–NIF 1:1.