Fixed Dose Single Tablet Formulation with Differential Release of Amlodipine Besylate and Simvastatin and Its Pharmacokinetic Profile: QbD and Risk Assessment Approach

Figures & data

Figure 1 Schematics for study design.

Table 1 Composition of AML-B and SIM Tablets for Pilot Study

Ingredient (per Tablet)	Amount	AML-B					SIM
		AB-4	AB-5	AB-6	AB-7	AB-8	S3	S4	S5	S6
Drug	Mg	7	7	7	7	7	10	10	10	10
Eudragit RSPO^®	%	10	15	20	25	30	–	–	–	–
	mg	20	30	40	50	60	–	–	–	–
Eudragi S-100^®	%	–	–	–	–	–	1	2	3	5
	mg	–	–	–	–	–	2	4	6	10
DCP	%	79.5	74.5	69.5	64.5	59.5	93	92	91	89
	mg	159	149	139	129	119	186	184	182	178

Table 2 Design Matrix for Optimization of Amlodipine Tablet

Experimental Runs	A:Polymer (mg)	B: DCP (mg)
1	25.00	154.00
2	15.00	164.00
3	15.00	164.00
4	20.00	159.00
5	20.00	159.00
6	25.00	154.00
7	17.50	161.50
8	22.50	156.50

Table 3 Quality Target Product Profile and Identification of Critical Quality Attributes

Quality Attributes of Drug Product	Target		Is It CQAs?	Justification
Dosage form	Modified release Oral formulation		Yes	Modified dosage form Have minimum fluctuation in bioavailability.
Administration Route	Oral		Yes	Oral route of administration is preferred.
Dosage design	Tablets		Yes	It was objective to formulate Fixed dose matrix tablet.
Physical Characteristics of Tablets	Appearance	–	No	Appearance is not critical factor only meant for patient acceptability.
	Friability	< 1%	Yes	Friability is critical factor as affecting s release of drug.
	Thickness (mm)		Yes	For packaging tablet thickness is a critical factor.
	Hardness (Kp)		Yes	Hardness is critical factor as affecting tablet disintegration and, dissolution rate.
	% Yield		Yes	% Yield should be maximum and formulation factor affects % yield it is critical factor.

Table 4 FMEA Risk Assessment of Fixed Dose Single Tablet Formulation of Amlodipine Besylate and Simvastatin

Formulation/Process Parameter		Failure Mode	Failure Effect	Severity (S)	Root of Failure	Probability (O)	Detectability	Detectability	RPN
Formulation process	Polymer concentration	Inappropriate concentration	Drug release	3	Improper selection of concentration	3	% Yield and Friability	2	18
	Drug concentration	Inappropriate concentration	Drug release	3	Improper selection of concentration	3	% Yield	2	18
	Granulating liquid	Inappropriate liquid amount	Drug release	3	Improper selection of amount	3	% Yield	1	9

Table 5 Composition of Fixed Dose Tablet Formulation of AML-B and SIM

AML-B		SIM
Ingredients	Quantity for 500 Tablets	Ingredients	Quantity for 500 Tablets
AML-B (g)	3.5	SIM (g)	5.0
Dibasic calcium phosphate (g)	36.99	Dibasic calcium phosphate (g)	44.0
Eudragit^® RSPO (g)	6.01	Eudragit^® RSPO (g)	0.5
PVP K-30^® (g)	3.0	Magnesium stearate (g)	0.5
Magnesium stearate (g)	0.5	Isopropyl alcohol (mL)	30–35
Isopropyl alcohol (mL)	30–35
Total (g)	50.0	Total (g)	50.0

Table 6 Physical Characteristics of AML-B and SIM Tablets

Methods	Features	AML		SIM
		Mean	SD	Mean	SD
Water based wet granulation	Thickness (mm)	3.504	0.946	3.376	0.898
	Diameter (mm)	7.896	0.018	7.918	2.614
	Hardness (Kp)	4.64	1.407	5.42	1.29
IPA-based granulation	Thickness (mm)	3.3881	0.405	3.332	0.503
	Diameter (mm)	7.897	1.702	7.906	2.23
	Hardness (Kp)	9.99	2.85	9.2	0.64

Table 7 Physical Characteristics of Pilot Batches of AML-B and Simvastatin (Mean n = 10)

Characteristics	AML-B					SIM
	AB4	AB5	AB6	AB7	AB8	S3	S4	S5	S6
Thickness (mm)	2.53	2.60	2.70	2.77	2.91	2.20	2.17	2.22	2.21
Diameter (mm)	7.93	7.92	7.92	7.91	7.91	7.94	7.93	7.93	7.92
Hardness (Kp)	10.3	10.9	12.6	11.1	10.3	4.2	6.2	8.2	9.3

Table 8 In-vitro Release at Different Time Intervals of AML-B Tablets with R² Values of Release Models

Parameters			% Drug Released (Average of 3 Tablets)
			AB-4	AB-5	AB-6	AB-7	AB-8
Release models	Zero order		0.978	0.9841	0.979	0.982	0.969
	First order		0.9977	0.9984	0.9923	0.9944	0.9572
	Higuchi		0.9991	0.9997	0.9973	0.9986	0.9622
	Korsmeyer Peppas	R^2	0.9991	0.9996	0.9982	0.9993	0.9794
		n	0.49	0.51	0.52	0.54	0.51

Figure 2 Combined effect of Eudragit and DCP on the release of AML-B at different time intervals in: (A) screening study and (B) optimization study.

Figure 3 Behavior of simvastatin tablets after 2 h exposure (A) 0.01 N HCl (B) phosphate buffer.

Figure 4 In-vitro release of tablets at different time intervals (A) AML-B tablets in 0.1 N HCL (B) SIM tablets in 0.1 N HCL + 0.5% sodium dodecyl sulfate and SIM tablets in phosphate buffer containing 0.5% sodium dodecyl sulfate.

Table 9 Release of Different Formulation of AML-B at Specified Time Intervals (Mean, n = 3)

Run	Component		Response
	1	2	1	2	3	4	5
	A: Polymer	B: DCP	Rel_at_1h	Rel_at_2h	Rel_at_4h	Rel_at-6h	Rel_at_8h
1	25	154	28.39	37.52	48.3	62.61	76.55
2	15	164	29.61	43.06	59.8	73.25	84.68
3	15	164	28.39	45.79	74.4	88.05	93.44
4	20	159	30.69	42.63	64.84	83.24	91.86
5	20	159	30.19	43.2	67.14	79.22	88.67
6	25	154	26.6	36.87	49.24	60.82	75.45
7	17.500	161.500	29.69	44.49	75.04	96.1	101.21
8	22.500	156.500	28.68	38.82	58.15	74.04	87.41

Table 10 Physical Characteristics and In-vitro Release of Validation Formulation of AML-B Tablet

Statistics:	Thickness (mm)	Diameter (mm)	Hardness (Kp)	% Drug Release
				Observed	Desired
Xmax	2.66 ± 0.04	7.97 ± 0.02	12.1 ± 0.5	–	–
Xmin	2.38 ± 0.08	7.95 ± 0.01	8.4 ± 0.3	–	–
Xi/n	2.54 ± 0.06	7.96 ± 0.07	9.9 ± 0.6	–	–
Xrel (%)	3.31 ± 0.03	0.09 ± 0.09	13.4 ± 0.4	–	–
Time (min)				–	–
60	–	–	–	25.59 ± 0.3	15–25
120	–	–	–	35.4 ± 0.4	25–40
240	–	–	–	48.63 ± 0.3	35–60`
360	–	–	–	61.67 ± 0.3	50–80
480	–	–	–	70.55 ± 0.2	Not less than 80

Figure 5 Factor levels adjustment to achieve predicted release at (A) 1 h (B) 2 h (C) 4 h (D) 6 h (E) 8 h.

Figure 6 (A) Release profile of validated formulation (B) In-vitro drug release of fixed dose tablet of AML-B and SIM.

Table 11 Percentage Recovery, Intraday and Inter-Day Accuracy, Precision of AML-B and SIM

Drug	Conc. ng/mL	% Recovery (n=3)	RSD	Intra-Day Accuracy (n = 5)	Precision	Inter-Day Accuracy (n=5)	Precision
AML-B	5	92.858	0.172	92.828	0.131	92.485	0.903
	30	96.247	0.011	96.260	0.023	96.725	0.987
	50	101.538	0.013	101.535	0.017	102.563	1.677
SIM	0.2	117.754	0.309	117.682	0.273	102.563	0.273
	0.6	108.754	0.152	108.568	0.126	108.568	0.126
	2.0	94.515	0.060	94.517	0.042	94.517	0.042

Figure 7 Plasma concentration vs time of FDC AML-B (5 mg) and SIM (10 mg) after a single oral administration in dogs (n=6).

Figure 8 Mean plasma concentration vs time of fixed dose combination AML-B (5 mg) and SIM (10 mg) after a single oral administration in dogs (n = 6).

Table 12 Pharmacokinetic Parameters of AML-B and SIM After Oral Administration of Fixed Dose

Parameter	Mean ± SD values of Pharmacokinetic Parameters of
	AML-B	SIM
Cmax (ng/mL)	46.37 ± 12.19	4.07 ± 1.14
tmax (h)	12 ± 0	8 ± 0
tlag (h)	0 ± 0	6.33 ± 0.81
AUC0-∞ (ng/mL*h)	1225.69 ± 608.86	44.61 ± 20.18
AUCt-∞(ng/mL*h)	187.60 ± 203.93	2.75 ± 2.05
%AUC t-∞(ng/mL*h)	13.67 ±7.44	5.66 ± 2.941``
MRT (h)	24.30 ± 6.87	16.02 ± 3.36
Kelim (1/h)	0.05 ± 0.06	0.12 ± 0.07
t1/2 (h)	13.03 ± 4.82	7.12 ± 3.88
Vd (L)	82.90 ± 19.75	2.31 ± 0.75
Vss (L)	111.07 ± 34.76	4.21 ± 1.55
Cl (l/h)	5.11 ± 2.97	0.27 ± 0.15