Simvastatin-Nicotinamide Co-Crystals: Formation, Pharmaceutical Characterization and in vivo Profile

Figures & data

Table 1 Compositions of SIM-NIC Co-Crystals in Molar Ratios

Co-Crystals	Molar Ratio		Method
	SIM	NIC
F01	1	1	Dry grinding
F02	1	1	Liquid-assisted grinding
F03	1	1	Slurry
F04	1	1	Solvent evaporation
F05	1	2	Dry grinding
F06	1	2	Liquid-assisted grinding
F07	1	2	Slurry
F08	1	2	Solvent evaporation
F09	1	4	Dry grinding
F10	1	4	Liquid-assisted grinding
F11	1	4	Slurry
F12	1	4	Solvent evaporation

Table 2 Micromeritic Properties of Formulated SIM-NIC Co-Crystals

Parameters	tanɵ^−1	HR	CI
Pure Drug	31.47±0.287	1.18±1.599	15.58±1.395
F01	23.49±1.094	1.05±0.030	4.74±2.759
F02	23.31±0.754	1.17±0.094	13.94±7.113
F03	23.10±0.276	1.07±0.040	6.11±3.515
F04	23.08±0.213	1.14±0.074	11.89±5.650
F05	23.28±0.029	1.22±0.058	17.75±3.951
F06	21.06±1.150	1.20±0.183	15.33±12.151
F07	22.24±0.008	1.10±0.024	9.26±2.031
F08	22.94±0.775	1.14±0.089	12.01±7.145
F09	23.10±1.084	1.05±0.041	4.79±3.814
F10	22.41±0.652	1.08±0.024	7.42±2.010
F11	23.08±1.076	1.05±0.021	4.67±1.863
F12	23.51±1.225	1.18±0.071	15.09±5.117

Note: Data is presented as mean ± SD.

Figure 1 Comparative dissolution profile of SIM and all co-crystal formulations in acidic and basic media.

Figure 2 Zeta sizer analysis of F02; SIM:NIC (1:1), F07; SIM:NIC (1:2) and F11; SIM:NIC (1:4).

Figure 3 FTIR of SIM and co-crystals formulations F02; SIM:NIC (1:1), F07; SIM:NIC (1:2) and F11; SIM:NIC (1:4).

Figure 4 PXRD spectra of SIM and co-crystals formulations F02; SIM:NIC (1:1), F07; SIM:NIC (1:2) and F11; SIM:NIC (1:4).

Figure 5 DSC analysis (A) and TGA (B) of (a) SIM and co-crystals formulations (b) F02; SIM:NIC (1:1), (c) F07; SIM:NIC (1:2) and (d) F11; SIM:NIC (1:4).

Figure 6 SEM analysis; SIM at 100x (A), SIM:NIC (1:4) co-crystals at 100x (B) and at 1000x (C).

Table 3 Pharmacokinetic Parameters Following Oral Administration of SIM and SIM-GLU (F11) co-crystals to Healthy Rabbits (n=12)

Sr. No	Pharmacokinetic Parameters	Simvastatin	SIM-NIC (F11)
1	Cmax (µg/mL)	1.28±0.049	3.06±0.073
2	Tmax (hr)	1.50±0.000	1.50±0.000
3	AUC(0-∞) μg/mL*min	94.82±2.593	450.79±1.658
4	AUMC(0-∞) μg/mL*min2	18,777.91±578.20	102,333.27±970.13
5	Kel (hr-1)	0.34±0.006	0.18±0.008
6	t 1/2 (hr)	2.04±0.036	3.90±0.182
7	MRT (hr)	3.30±0.236	3.78±0.124
8	Vz (L)	74.46±2.991	30.00±1.449
9	Cl (Lmin-1)	0.42±0.009	0.09±0.000

Note: Data is presented as mean ± SD.

Figure 7 Mean ± SD Plasma concentration time profile of SIM and SIM: NIC co-crystals (n=12).