Preparation and characterization of silymarin synchronized-release microporous osmotic pump tablets

Figures & data

Figure 1 The XRPD graphs of SM API (A), phospholipids (B), the physical mixture of SM API/phospholipids (C), and SM-PC (D).

Abbreviations: XPRD, X-ray powder diffraction; SM API, SM active pharmaceutical ingredient; SM-PC, SM phytosome complex; CPS, counts per second.

Figure 2 DSC thermograms of SM API (A), phospholipids (B), the physical mixture of SM API/phospholipids (C), and SM-PC (D).

Abbreviations: DSC, differential scanning calorimetry; SM API, SM active pharmaceutical ingredient; SM-PC, SM phytosome complex.

Figure 3 Infrared spectroscopy of SM API (A), phospholipids (B), the physical mixture of SM API/phospholipids (C), and SM-PC (D).

Abbreviations: SM API, SM active pharmaceutical ingredient; SM-PC, SM phytosome complex.

Table 1 Solubility of SM in different mediums

Sample	Solvent	Solubility (µg/mL)
		TF	SC	SD	SB	ISB
SM	pH 1.2 hydrochloric acid solution	58.3±0.23	42.6±0.41	12.3±0.86	9.6±0.89	3.5±0.34
	distilled water (pH 5.6)	61.4±0.14	58.8±0.72	19.2±0.80	12.9±0.91	4.3±0.28
	pH 6.8 phosphate buffer	106.0±0.57	108.5±1.53	37.2±0.45	33.4±0.21	9.6±1.36
	pH 7.5 phosphate buffer	125.5±0.46	168.5±2.25	42.7±0.39	102.2±0.89	49.8±2.27
	0.5% SDS solution	159.3±0.14	451.4±1.23	110.4±0.47	406.1±1.04	229.2±0.77
SM-PC	pH 1.2 hydrochloric acid solution	49.0±0.35	49.7±0.27	10.4±0.71	68.3±0.48	14.8±0.72
	distilled water (pH 5.6)	80.3±0.84	204.9±1.12	35.4±1.17	312.6±0.91	61.2±0.78
	pH 6.8 phosphate buffer	102.3±0.87	257.1±1.53	58.7±1.86	414.4±0.71	85.0±1.17
	pH 7.5 phosphate buffer	97.4±0.68	315.7±1.58	66.8±0.19	479.2±0.49	84.5±1.62
	0.5% SDS solution	152.3±1.94	551.4±1.18	121.4±0.97	908.7±1.84	260.2±1.71

Note: Data shown as mean ± standard deviation.

Abbreviations: TF, taxifolin; SC, silychristin; SD, silydianin; SB, silybin; ISB, isosilybin; SM, silymarin; SM-PC, SM phytosome complex; SDS, sodium dodecyl sulfate.

Table 2 The apparent oil–water partition coefficient of SM

Sample	Solvent	Log P
		TF	SC	SD	SB	ISB
SM	pH 1.2 hydrochloric acid	1.59±0.04	1.20±0.08	1.02±0.02	0.81±0.07	0.95±0.11
	pH 4.5 acetate buffer	1.26±0.09	1.16±0.07	0.88±0.07	0.76±0.09	0.83±0.07
	Distilled water (pH 5.6)	1.22±0.12	0.87±0.09	0.81±0.04	0.64±0.04	0.68±0.05
	pH 6.8 phosphate buffer	0.57±0.07	0.64±0.11	0.74±0.07	0.46±0.06	0.52±0.07
	pH 7.5 phosphate buffer	0.44±0.08	0.61±0.05	0.65±0.03	0.32±0.14	0.45±0.02
	pH 8.0 phosphate buffer	0.34±0.02	0.48±0.10	0.28±0.08	0.28±0.05	0.22±0.03
SM-PC	pH 1.2 hydrochloric acid	1.80±0.14	1.91±0.17	1.64±0.04	2.12±0.05	2.20±0.10
	pH 4.5 acetate buffer	1.77±0.11	1.74±0.25	1.55±0.15	1.88±0.07	1.79±0.02
	Distilled water (pH 5.6)	1.45±0.16	1.70±0.06	1.38±0.07	1.67±0.03	1.68±0.08
	pH 6.8 phosphate buffer	1.20±0.09	1.51±0.13	1.17±0.09	1.65±0.16	1.64±0.14
	pH 7.5 phosphate buffer	0.98±0.15	1.18±0.08	1.14±0.06	1.53±0.18	1.45±0.07
	pH 8.0 phosphate buffer	0.89±0.07	1.16±0.10	1.11±0.16	1.49±0.21	1.32±0.09

Note: Data shown as mean ± standard deviation.

Abbreviations: TF, taxifolin; SC, silychristin; SD, silydianin; SB, silybin; ISB, isosilybin; SM, silymarin; SM-PC, SM phytosome complex.

Figure 4 Release profiles of three preparations in pH 7.5 phosphate buffer solutions (containing 0.5% SDS).

Notes: (A) SM API, (B) SM-PC, and (C) silymarin capsule. The detailed statistical analysis results are shown in the Table S1.
Abbreviations: SM, silymarin; SM API, SM active pharmaceutical ingredient; SM-PC, SM phytosome complex, TF, taxifolin; SC, silychristin; SD, silydianin; SB, silybin; ISB, isosilybin; SDS, sodium dodecyl sulfate.

Figure 5 Schematic diagram of drug dissolution of SM MPOP.

Notes: (A) The original state of MPOP. (B) When contacting the dissolution medium, micropores form on the membrane of MPOP. (C) Some water molecules enter the core tablet and some drugs dissolve. (D) As more water enters the core tablet, more drugs dissolve. (E) All drugs completely dissolve and make a high osmotic pressure in the core tablet. (F) The high osmotic pressure becomes a driving force to trigger the release of all the components in the core tablet at a consistent rate.
Abbreviations: MPOP, microporous osmotic pump; SM MPOP, silymarin MPOP; SM-PC, SM phytosome complex.

Table 3 Factors and levels of the orthogonal experiment

Factor	A (%)	B (%)	C (%)
Level 1	30	40	3
Level 2	35	45	3.5
Level 3	40	50	4

Table 4 Results of the orthogonal experiment

Number	Factor			L (%)
	A (%)	B (%)	C (%)
1	1	1	1	31.6
2	1	2	2	21.0
3	1	3	3	23.9
4	2	1	2	21.1
5	2	2	3	32.3
6	2	3	1	38.4
7	3	1	3	19.4
8	3	2	1	32.2
9	3	3	2	7.7
K1	25.5	24.0	34.1
K2	30.6	28.5	16.6
K3	19.8	23.3	25.7
R	10.8	5.1	17.5

Notes: K₁, K_2, and K₃ are the average scores of level 1, level 2, and level 3 for each factor; R is the range among the average scores of Level 1, Level 2, and Level 3 for each factor.

Table 5 Results of variance analysis

Factor	Sum of squared deviations	Variance	F	F critical values of F	Significance
A	176.7	2	18.9	19.0	P>0.05
B	46.8	2	5.0	19.0	P>0.05
C	458.4	2	49.1	19.0	P<0.05
Deviation	9.3	2

Table 6 f₂ values of different batches

Batch 1	Batch 2	Active components
		TF	SC	SD	SB	ISB
130702	130703	81.64	85.48	85.76	80.67	81.72
103703	130704	73.84	88.24	79.86	89.90	75.25
130702	130704	76.87	84.02	78.37	89.56	86.08

Abbreviations: TF, taxifolin; SC, silychristin; SD, silydianin; SB, silybin; ISB, isosilybin.

Table 7 Curve fitting for drug dissolution of SM MPOP

Model	Active components	Fitting equation	r
Zero order	TF	=7.357t+3.714	0.9969
	SC	Mt/M∞=7.446t+1.835	0.9983
	SD	Mt/M∞=7.745t+2.592	0.9975
	SB	Mt/M∞=7.171t+2.071	0.9988
	ISB	Mt/M∞=7.253t+2.578	0.9976
First order	TF	ln (1−Mt/M∞)=−0.185t+4.501	0.9884
	SC	ln (1−Mt/M∞)=−0.189t+4.959	0.9762
	SD	ln (1−Mt/M∞)=−0.185t+4.554	0.9752
	SB	ln (1−Mt/M∞)=−0.172t+4.558	0.9762
	ISB	ln (1−Mt/M∞)=−0.171t+4.535	0.9849
Higuchi	TF	Mt/M∞=26.227t^1/2−8.390	0.9785
	SC	Mt/M∞=26.022t^1/2−10.464	0.9670
	SD	Mt/M∞=25.905t^1/2−10.650	0.9715
	SB	Mt/M∞=25.307t^1/2−10.189	0.9674
	ISB	Mt/M∞=25.396t^1/2−9.561	0.9716

Abbreviations: SM MPOP, silymarin microporous osmotic pump; TF, taxifolin; SC, silychristin; SD, silydianin; SB, silybin; ISB, isosilybin.

Table 8 Release profiles of osmotic pressure in different medium

Medium	Π	Δπ	Release rate of active components (mg·h^−1)
(mol·L^−1)	(Osmol·kg^−1)	(Osmol·kg^−1)	TF	SC	SD	SB	ISB
Distilled water	0.000	2.200	7.357	7.446	7.745	7.801	7.253
Sodium chloride (0.15)	0.310	1.890	6.445	6.518	6.828	6.903	6.358
Sodium chloride (0.30)	0.600	1.600	5.522	5.516	5.89	6.08	5.372
Sodium chloride (0.55)	0.971	1.229	4.51	4.554	4.912	4.835	4.317
Sodium chloride (0.70)	1.203	0.997	3.568	3.687	3.925	4.087	3.405

Abbreviations: TF, taxifolin; SC, silychristin; SD, silydianin; SB, silybin; ISB, isosilybin.

Table 9 f₂ values of SM-PC MPOP and SM HPMC tablets in pH 7.5 phosphate buffer solution (contain 0.5% SDS)

Effective components	pH 7.5 phosphate buffer solution (0.5% SDS)
	A	B	C
TF/SC	75.74	61.17	73.25
TF/SD	73.74	68.85	45.32
TF/SB	72.68	60.75	33.47
TF/ISB	66.87	55.57	41.29
SC/SD	79.97	80.07	53.70
SC/SB	85.36	74.86	36.91
SC/ISB	79.47	81.52	46.60
SD/SB	81.23	77.04	49.78
SD/ISB	76.21	68.06	65.39
SB/ISB	85.17	83.15	56.29

Abbreviations: SM-PC MPOP, silymarin phytosome complex microporous osmotic pump; SM HPMC, silymarin hydroxypropyl methylcellulose; TF, taxifolin; SC, silychristin; SD, silydianin; SB, silybin; ISB, isosilybin; SDS, sodium dodecyl sulfate.

Figure 6 Release profiles in pH 7.5 phosphate buffer solution (containing 0.5% SDS).

Notes: (A) SM-PC MPOP tablet, (B) SM MPOP tablet, and (C) SM HPMC tablet.
Abbreviations: SM-PC MPOP, silymarin phytosome complex microporous osmotic pump; SM HPMC, silymarin hydroxypropyl methylcellulose; TF, taxifolin; SC, silychristin; SD, silydianin; SB, silybin; ISB, isosilybin; SDS, sodium dodecyl sulfate.

Table S1 Statistical analyses of the release profile among three drugs

Time (minutes)	Cumulative dissolution (%)
	TF	SC	SD	SB	ISB
SM API
0	0.00±0.00	0.00±0.00	0.00±0.00	0.00±0.00	0.00±0.00
10	27.44±0.81	29.72±1.37	19.87±4.41	17.16±2.87	16.49±4.74
20	39.69±1.17	33.32±4.13	22.49±1.87	20.82±0.93	18.50±4.98
30	51.83±5.87	41.10±6.84	27.59±2.37	23.11±0.96	21.11±4.19
40	56.20±1.65	47.77±4.54	32.55±3.42	25.90±1.32	24.52±4.34
50	63.24±1.86	55.64±8.29	38.28±3.64	28.28±3.15	28.44±4.29
60	68.49±2.01	59.19±5.60	42.16±1.67	31.91±2.15	31.83±4.37
SM-PC
0	0.00±0.00	0.00±0.00	0.00±0.00	0.00±0.00	0.00±0.00
10	53.05±7.43*	51.14±4.22*	37.43±3.79*	25.87±3.92*	31.75±0.57*
20	68.07±5.09*	63.93±3.38*	50.98±4.91*	44.52±6.52*	50.51±6.58*
30	79.70±4.62*	76.37±3.07*	69.58±2.39*	62.71±4.98*	74.41±7.59*
40	85.98±1.27*	80.63±3.56*	77.69±1.79*	73.62±6.90*	82.84±5.88*
50	91.75±2.10*	88.72±1.35*	85.49±1.98*	81.45±7.34*	86.38±6.02*
60	95.45±1.58*	92.93±0.96*	90.20±1.58*	88.76±4.84*	90.72±6.76*
Silymarin capsule
0	0.00±0.00	0.00±0.00	0.00±0.00	0.00±0.00	0.00±0.00
10	57.93±4.63	57.25±2.86	30.74±1.39#	29.62±1.63	43.66±1.54#
20	79.99±6.40	67.63±3.38	56.95±2.58#	64.44±3.54#	66.78±2.35#
30	90.71±4.89#	83.79±4.19	78.32±3.54#	76.43±4.20#	86.58±3.05#
40	92.99±4.87#	90.33±4.52#	89.68±4.06#	81.70±4.48	93.35±3.29#
50	94.05±5.19	92.40±4.62	91.17±4.12	88.54±4.86	95.14±3.35
60	95.48±5.32	93.94±4.70	93.69±4.24	90.47±4.97	96.41±3.40

Notes:

* Significance between A-silymarin and B-silymarin phospholipid complex.

# Significance between B-silymarin phospholipid complex and C-silymarin capsule. Data shown as mean ± standard deviation.

Abbreviations: SM API, silymarin active pharmaceutical ingredient; SM-PC, silymarin phytosome complex; TF, taxifolin; SC, silychristin; SD, silydianin; SB, silybin; ISB, isosilybin.