Methodological assessment of the reduction of the content of impurities in nimodipine emulsion via the use of 21 amino acid protection

Figures & data

Figure 1 The chemical structure of emulsion and its impurity: (A) NMP, (B) impurity A, (C) impurity B and (D) impurity C.

Abbreviation: NMP, nimodipine.

Figure 2 Destructive principle of NMP emulsion: (A) acid, (B) base, (C) oxidation, (D) temperature and (E) light.

Abbreviation: NMP, nimodipine.

Figure 3 The effect of pH value of aqueous phase/coarse/final emulsions on the impurities A and C: (A) impurity A and (B) impurity C.

Abbreviation: pH, potential of hydrogen.

Table 1 The increased percentage of impurities of oil phase/aqueous phase/emulsion prior to and following sterilization

Measurement object	Increased percentage of impurities before and after sterilization
	Impurity A	Impurity C
Oil phase	0.091	0.04
Aqueous phase	0.407	0.05
Total	0.498	0.09
NMP emulsion	0.4839	0.095

Abbreviation: NMP, nimodipine.

Table 2 The content of impurities of emulsions with sodium bisulfite and/or sodium thiosulfate

Antioxidant (0.1%)	Impurity A (%)	Impurity C (%)
Sodium bisulfate	20.188	0.299
Sodium metabisulfite	22.815	0.306

Table 3 The fluctuation of pH value of emulsion in the presence of methionine and in the absence of amino acids

pH	Aqueous phase	Coarse emulsion	pH value	Final emulsion	pH value	Emulsion after sterilization
With methionine	7.5	7.4	Left untreated	7.3	Left untreated	7.3
Without methionine	7.5	6.0	Adjusted to 7.2	6.0	Adjusted to 7.0	5.3

Abbreviation: pH, potential of hydrogen.

Table 4 The amount of impurities in emulsions containing different amino acids

No	Amino acids	Structure	Impurity A (%)	Impurity C (%)
1	Glycine		0.938	0.322
2	Alanine		0.877	0.327
3	Valine		0.769	0.320
4	Threonine		0.716	0.328
5	Cysteine		3.795	0.401
6	Cystine		0.745	0.321
7	Leucine		0.589	0.320
8	Isoleucine		0.727	0.336
9	Asparagine		0.596	0.325
10	Serine		0.485	0.268
11	Methionine		0.628	0.309
12	Glutamine		0.658	0.321
13	Tryptophan		1.062	0.315
14	Phenylalanine		1.023	0.345
15	Histidine		0.934	0.322
16	Tyrosine		0.798	0.339
17	Arginine		0.636	0.311
18	Lysine		0.594	0.306
19	Proline		0.583	0.316
20	Aspartate		1.101	0.325
21	Glutamate		0.774	0.302

Table 5 The content of impurities of emulsions in the presence of different pH-adjusting agents

Amino acid	pH-adjusting agent (0.1 mol/L)	pH value	Impurity A (%)	Impurity C (%)
Cysteine	Sodium hydroxide solution	7.2	3.795	0.401
	Potassium hydroxide solution		3.729	0.396
	Ethylenediamine solution		3.087	0.351
Histidine	Hydrochloric acid solution		0.934	0.322
	Acetic acid solution		0.622	0.274

Abbreviation: pH, potential of hydrogen.

Figure 4 The content of impurities of emulsion containing different amino acids under different pH values: (A) impurity A and (B) impurity C.

Abbreviation: pH, potential of hydrogen.

Table 6 The content of impurities of emulsions using lysine and leucine as antioxidants

Lysine and leucine		Impurity A (%)	Impurity C (%)
Total dosage (%)	Proportion
0.05	1:1	0.789	0.296
0.1		0.300	0.265
0.2		0.836	0.304
0.1	1:9	0.301	0.260
	2:8	0.352	0.261
	3:7	0.283	0.267
	4:6	0.244	0.254
	5:5 (1:1)	0.302	0.268
	6:4	0.290	0.258
	7:3	0.326	0.261
	8:2	0.367	0.265
	9:1	0.285	0.263

Table 7 The content of impurities A and C in six NMP emulsions

No	Impurity A (%)	RSD (impurity A, %)	Impurity C (%)	RSD (impurity C, %)
1	0.251	0.02	0.247	0.02
2	0.247		0.252
3	0.252		0.254
4	0.245		0.252
5	0.249		0.244
6	0.246		0.248

Abbreviations: NMP, nimodipine; RSD, relative standard deviation.

Table 8 The content of impurities and consumption of sodium hydroxide solution

Adjusting way	Impurity C (%)	Impurity A (%)	Consumption of sodium hydroxide solution (mL)
Adjusting pH value	0.336	1.063	1
Antioxidants
NaHSO3/Na2S2O5	0.299–0.306	20.188–22.815	4–5
Amino acids	0.268–0.345	0.485–1.101	0.2–0.5

Abbreviation: pH, potential of hydrogen.