Design of experiments assisted the development of inclusion complexes of ramipril using hydrophilic carriers for enhancement of solubility and dissolution rate

Mohammad, Azeez; Singh, Sumer; Swain, Suryakanta; Parhi, Rabinarayan

doi:10.1590/s2175-97902022e20203

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Brazilian Journal of Pharmaceutical Sciences

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Article • Braz. J. Pharm. Sci. 58 • 2022 • https://doi.org/10.1590/s2175-97902022e20203 copy

Design of experiments assisted the development of inclusion complexes of ramipril using hydrophilic carriers for enhancement of solubility and dissolution rate

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

The goal of the present study was to develop inclusion complexes and polymers dispersions of ramipril prepared by physical mixing, kneading, co-evaporation, and solvent evaporation methods to enhance drug solubility and dissolution rate, and thereby to reduce drug dose and side effects using selected hydrophilic carriers such as β-CD, PVP-K25, PEG 4000, and HPMC K100M. The prepared formulations were characterized for solubility and in-vitro drug release studies. The systematic optimization of formulations was performed using I-Optimal experimental design by selecting factors such as type of carriers (X1), drug: carrier ratio (X2), and method of preparation (X3), and response variables including percent yield (Y1), solubility (Y2), Carr’s index (Y3) and drug release in 30 min (Y4). Mathematical modeling was carried out using a quadratic polynomial model. The inclusion complex formulation (F27) was selected as an optimized batch by numerical desirability function and graphical optimization with the help of design space. The inclusion complex prepared by the co-evaporation method showed maximum drug solubility and released in pH 6.8 phosphate buffer compared to pure and other formulations. The inclusion complex is a feasible approach to improve the solubility, dissolution rate, bioavailability, and minimization of drugs’ gastrointestinal toxicity upon oral administration of ramipril.

Keywords:
Ramipril; β-cyclodextrin; Inclusion complexes; I-optimal design; Solubility; X-RD; In-vitro drug release

Formulation code (F0-F12)	Drug: polymer ratio (Physical mixing Method)	Formulation code (F13-F24)	Drug: polymer ratio (Kneading method)	Formulation code (F25-F36)	Drug: polymer ratio (Co-evaporation method)	Formulation code (F37-F48)	Drug: polymer ratio (Solvent evaporation method)
F0	Pure drug (1 part)	F13	Drug : β-CD (1:1)	F25	Drug : β-CD(1:1)	F37	Drug : β-CD (1:1)
F1	Drug : β-CD (1:1)	F13	Drug : β-CD (1:1)	F25	Drug : β-CD(1:1)	F37	Drug : β-CD (1:1)
F2	Drug : β-CD (1:2)	F14	Drug : β-CD(1:2)	F26	Drug : β-CD(1:2)	F38	Drug : β-CD (1:2)
F3	Drug : β-CD (1:4)	F15	Drug : β-CD(1:4)	F27	Drug : β-CD(1:4)	F39	Drug : β-CD (1:4)
F4	Drug : PEG 4000 (1:1)	F16	Drug : PEG 4000(1:1)	F28	Drug : PEG 4000(1:1)	F40	Drug : PEG 4000 (1:1)
F5	Drug : PEG 4000 (1:2)	F17	Drug : PEG 4000(1:2)	F29	Drug : PEG 4000(1:2)	F41	Drug : PEG 4000 (1:2)
F6	Drug : PEG 4000 (1:4)	F18	Drug : PEG 4000(1:4)	F30	Drug : PEG 4000(1:4)	F42	Drug : PEG 4000 (1:4)
F7	Drug : PVP-K25 (1:1)	F19	Drug : PVP-K25(1:1)	F31	Drug : PVP-K25(1:1)	F43	Drug : PVP-K25 (1:1)
F8	Drug : PVP-K25 (1:2)	F20	Drug : PVP-K25(1:2)	F32	Drug : PVP-K25(1:2)	F44	Drug : PVP-K25 (1:2)
F9	Drug : PVP-K25 (1:4)	F21	Drug : PVP-K25(1:4)	F33	Drug : PVP-K25(1:4)	F45	Drug : PVP-K25 (1:4)
F10	Drug : HPMC K100M (1:1)	F22	Drug : HPMCK100 M (1:1)	F34	Drug : HPMC K100 M (1:1)	F46	Drug : HPMC K100 M (1:1)
F11	Drug : HPMC K100M (1:2)	F23	Drug : HPMC K100 M(1:2)	F35	Drug : HPMC K100 M(1:2)	F47	Drug : HPMC K100 M (1:2)
F12	Drug : HPMC K100M (1:4)	F24	Drug : HPMC K100 M(1:4)	F36	Drug : HPMC K100 M(1:4)	F48	Drug : HPMC K100 M (1:4)

Name of the factors	Type of factors	Factors Continuity	Levels of the factors
Name of the factors	Type of factors	Factors Continuity	L1	L2	L3	L4
X1: Type of carrier	Categorical	Nominal	PEG 4000	PVP-K25	β-CD	-
X2: Drug: carrier ratio	Numerical	Discrete	1:1	1:2	1:4	-
X3: Method of preparation	Categorical	Nominal	PM	KM	CM	SEM

ANOVA for Response Surface Reduced Quadratic model
Source	Sum of Squares	df	Mean Square	F Value	p-value Prob > F
Model	3160.49	11	287.32	4.09	0.0362	Significant
A-Type of carrier	2598.10	1	2598.10	37.02	0.0005
B-Drug: Carrier ratio	67.60	1	67.60	0.96	0.3591
C-Method of preparation	32.22	3	10.74	0.15	0.9245
AB	18.00	1	18.00	0.26	0.6281
AC	392.47	3	130.82	1.86	0.2239
A^2	8.10	1	8.10	0.12	0.7440
B^2	147.00	1	147.00	2.09	0.1911
Residual	491.30	7	70.19
Lack of Fit	366.30	5	73.26	1.17	0.5200	Not significant
Pure Error	125.00	2	62.50
Cor Total	3651.79	18

ANOVA for Response Surface Reduced Cubic model
Analysis of variance table [Classical sum of squares - Type II]
Source	Sum of Squares	df	Mean Square	F Value	p Value Prob > F
Model	9161.84	15	610.79	429.46	0.0002	Significant
A-Type of carrier	646.67	1	646.67	454.69	0.0002
B-Drug: Carrier ratio	672.40	1	672.40	472.78	0.0002
C-Method of preparation	1316.31	3	438.77	308.51	0.0003
AB	484.00	1	484.00	340.31	0.0003
AC	4146.36	3	1382.12	971.80	< 0.0001
BC	974.47	3	324.82	228.39	0.0005
A^2	87.02	1	87.02	61.19	0.0043
B^2	44.08	1	44.08	31.00	0.0114
AB^2	533.33	1	533.33	375.00	0.0003
Residual	4.27	3	1.42
Lack of Fit	4.27	1	4.27
Pure Error	0.000	2	0.000
Cor Total	9166.11	18

ANOVA for Response Surface Reduced Cubic model
Analysis of variance table [Classical sum of squares - Type II]
Source	Sum of Squares	df	Mean Square	F Value	p-value Prob > F
Model	1879.22	15	125.28	2.60	0.0349	Significant
A-Type of carrier	73.49	1	73.49	1.52	0.3051
B-Drug: Carrier ratio	275.84	1	275.84	5.71	0.0967
C-Method of preparation	501.20	3	167.07	3.46	0.1676
AB	113.85	1	113.85	2.36	0.2222
AC	121.00	3	40.33	0.84	0.5570
BC	234.07	3	78.02	1.62	0.3515
A^2	747.19	1	747.19	15.48	0.0293
B^2	21.01	1	21.01	0.44	0.5565
AB^2	113.34	1	113.34	2.35	0.2230
Residual	144.83	3	48.28
Lack of Fit	144.83	1	144.83
Pure Error	0.000	2	0.000
Cor Total	2024.05	18

ANOVA for Response Surface Reduced Cubic model
Analysis of variance table [Classical sum of squares - Type II]
Source	Sum of Squares	df	Mean Square	F Value	p-value Prob > F
Model	2533.72	15	168.91	9.04	0.0475	Significant
A-Type of carrier	22.77	1	22.77	1.22	0.3503
B-Drug: Carrier ratio	96.10	1	96.10	5.14	0.1082
C-Method of preparation	373.01	3	124.34	6.65	0.0770
AB	16.00	1	16.00	0.86	0.4231
AC	439.71	3	146.57	7.84	0.0623
BC	433.28	3	144.43	7.73	0.0635
A^2	99.22	1	99.22	5.31	0.1046
B^2	1474.08	1	1474.08	78.87	0.0030
AB^2	21.33	1	21.33	1.14	0.3637
Residual	56.07	3	18.69
Lack of Fit	56.07	1	56.07
Pure Error	0.000	2	0.000
Cor Total	2589.79	18

Run order	Build type	Factor X₁ (Type of Carrier)	Factor X₂ (Drug: Carrier Ratio)	Factor X3 (Method of Preparation)	Response 1 (Percent yield)	Response 2 (Solubility in mg/mL)	Response 3 (Carr’s Index)	Response 4 (Drug release in 30 min)
7	Model	PEG 4000	1:4	PM	56	54	28.34	45
8	Model	β-CD	1:4	PM	72	95	49.37	54
18	Replicate	PEG 4000	1:2	SEM	62	80	34.49	62
16	Model	β-CD	1:1	SEM	68	52	34.22	67
19	Model	β-CD	1:4	SEM	81	60	38.47	55
14	Model	β-CD	1:2	CM	75	89	16.67	78
2	Model	β-CD	1:1	PM	85	40	17.5	62
1	Model	PEG 4000	1:1	PM	60	43	17.81	61
5	Replicate	PVP-K25	1:2	PM	67	48	44.45	83
13	Model	PEG 4000	1:2	CM	45	12	20.84	78
4	Model	PVP-K25	1:2	PM	62	48	44.45	83
3	Lack of Fit	PEG 400	1:2	PM	40	26	21.88	84
10	Model	β-CD	1:2	KM	89	45	39.4	77
12	Model	PVP-K25	1:1	CM	70	34	28.58	56
9	Model	PEG 400	1:1	KM	50	78	25	82
15	Model	PVP-K25	1:4	CM	56	65	36.37	76
17	Model	PEG 400	1:2	SEM	47	80	34.49	62
11	Model	PEG 400	1:4	KM	42	55	23.08	67
6	Lack of Fit	β-CD	1:2	PM	68	85	13.8	81

Serial Number	Factor X₁ (Type of Carrier)	Factor X₂ (Drug: Carrier Ratio)	Factor X3 (Method of Preparation)	Response 1 (Percent yield)	Response 2 (Solubility in mg/mL)	Response 3 (Carr’s Index)	Response 4 (Drug release in 30 min)	Desirability
1	0.864	0.990	CM	76.096	94.394	37.052	74.792	1.000
2	0.852	1.000	CM	76.046	93.882	37.543	74.615	1.000
3	0.871	0.981	CM	76.077	94.683	36.668	74.980	1.000
4	0.878	0.991	CM	76.284	94.941	36.818	74.713	1.000
5	0.875	0.974	CM	76.031	94.834	36.386	75.146	1.000
6	0.877	0.998	CM	76.361	94.871	37.069	74.528	1.000

Formulation code	Solubility (µg/mL) (Mean ± S.D)	Percentage yield (%) (Mean ± S.D)	Drug content (%) (Mean ± S.D)
F25	54±1.54	73±2.07	29.00±1.89
F26	95±1.89	71±1.23	19.00±1.45
F27	120±1.54	74.20±1.76	59.75±1.34
F28	40±1.53	70.12±1.67	44.25±1.98
F29	43±1.76	71.14±1.98	41.09±1.43
F30	48±1.22	45.26±1.74	41.29±1.98
F31	52±0.99	10.50±1.12	14.19±1.57
F32	60±1.11	48.95±2.03	22.17±2.04
F33	89±2.00	10±1.94	19.75±1.23
F34	12±1.59	55.24±2.03	39.18±2.13
F35	22±1.98	48.19±1.83	40.78±2.03
F36	26±1.23	47.20±1.43	41.79±1.78

Formulation code	Angle of repose (ϴ) (Mean±S.D)	Carr’s index (%) (Mean±S.D)	Hausner’s ratio (Mean±S.D)	Bulk density (gm/cm³) (Mean±S.D)	Tapped density (gm/cm³) (Mean ± S.D)	Flow rate (mg/sec) (Mean ± S.D)
F0	45±0.85	52±0.42	3.10±0.63	2.15±1.51	11±0.92	100±1.23
F25	21.74±0.23	39.40±0.74	0.60±1.74	0.44±1.59	2±0.59	292±1.22
F26	28.65±1.23	28.58±1.76	0.71±1.41	0.50±1.25	3±0.72	710±1.34
F27	25.41±1.21	15±0.75	0.75±1.92	0.61±1.61	4.50±0.55	1236.60±1.33
F28	14.29±0.56	28.16±0.63	0.72±0.89	0.69±1.29	2.59±0.63	824.19±1.31
F29	19.18±0.53	29.18±0.42	0.62±0.86	0.75±1.53	3.18±0.82	642.23±1.30
F30	21.07±0.87	20.16±0.63	0.61±0.98	0.81±1.32	5.78±0.86	500.12±1.29
F31	13.56±0.98	36.37±0.41	0.63±0.85	0.19±1.92	0.70±0.93	30±1.32
F32	17.06±0.32	29.17±0.49	0.56±0.84	0.24±1.83	3.29±0.74	61.28±1.31
F33	26.16±0.59	37.50±0.62	0.62±1.11	0.20±1.90	1.50±0.82	125±1.39
F34	21.09±0.93	33.46±0.83	0.75±1.21	0.65±1.62	3.18±0.93	101.45±1.09
F35	22.78±0.73	37.15±0.41	0.71±1.09	0.52±1.52	6.23±0.77	85.26±1.15
F36	27.19±0.78	24.19±0.63	0.63±1.04	0.34±1.43	3.29±0.69	245.29±1.28

Formulation code	Zero order plot	First order plot	Higuchi plot	Koresmeyer-Peppa’s plot
Formulation code		R²		n
F0	0.8596	0.8933	0.9371	0.9509	0.903
F25	0.8011	0.8324	0.9154	0.9230	0.9411
F26	0.7246	0.8324	0.8626	0.9142	1.0495
F27	0.7478	0.9094	0.9272	0.8444	1.0426
F28	0.8879	0.9438	0.9634	0.8436	0.8197
F29	0.8793	0.9873	0.9947	0.8938	0.8234
F30	0.8535	0.9584	0.9452	0.8832	0.8647
F31	0.7315	0.8439	0.8569	0.8551	0.9291
F32	0.8409	0.9745	0.9829	0.8945	0.9120
F33	0.9052	0.9439	0.9706	0.9585	0.9559
F34	0.9383	0.9458	0.9625	0.8352	0.8214
F35	0.9520	0.9850	0.9780	0.8950	0.8457
F36	0.9799	0.9787	0.9945	0.8975	0.8761

Formulation	Before stability		After stability
	Drug content (%)* (Mean ± S.D)	Cumulative drug release (%)* (Mean ± S.D)	Drug content (%)* (Mean ± S.D)	Cumulative drug release (%)* (Mean ± S.D)
F27	59.75±0.09	88.74±0.12	60.02±0.56	88.45±0.03

Universidade de São Paulo, Faculdade de Ciências Farmacêuticas Av. Prof. Lineu Prestes, n. 580, 05508-000 S. Paulo/SP Brasil, Tel.: (55 11) 3091-3824 - São Paulo - SP - Brazil
E-mail: bjps@usp.br

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[1] *Correspondence: A. Mohammad. School of Pharmacy and Medical Sciences. Singhania University, Pacheri Bari, Jhunjhunu. Rajasthan-333515, India. Phone: +91-9885397747. E-mail: azeezmohammadphdscholar@ gmail.com.