Pharmaceutical Applications of Hot-Melt Extrusion: Part II

Figures & data

FIGURE 1. Release profiles of diltiazem hydrochloride from extruded pellets based on various polymers (polymer/drug ratio 1:1, size 2 × 2 mm). (▪) EC; (Δ) CAB; (⋄) Eudragit®; (•) EVAC.

FIGURE 2. The percentage phenylpropanolamine (PPA) released at 6 h from tablets containing 15% PPA, 30% Precirol, and 55% filler excipients prepared by hot-melt extrusion (HME) and high-shear melt granulation (MG). (□) Tablets compressed from granules within 20–40 mesh only; (▪) Tablets compressed from granules within 60–100 mesh only; (

) Tablets compressed from granules within 20–40 mesh but size-reduced to less than 60 mesh.

FIGURE 3. Stability of guaifenesin release rate from melt-extruded pellets (A) With out ethyl cellulose (B) With ethyl cellulose upon storage at 40C/75%RH in sealed HDPE containers with silica desiccants. Key: ▴ Initial; Δ 1 Month; ▪ 3 Months.

TABLE 1. Mean Pharmacokinetic Parameters (± SD) After Oral Administration of 300 mg Ibuprofen to Healthy Volunteers (n = 9): Ibu-slow® 600 (1/2 tablet), Mini-matrix F-1 Containing HPMC and Mini-matrix F-2 Containing Xanthan Gum

	Ibu-slow®	F-1	F-2
tmax (h)	2.7 ± 0.8	4.1 ± 0.9	6.4 ± 3.8
Cmax (μg/mL)	14.1 ± 3.4	7.8 ± 2.7^a	6.1 ± 1.1^a
AUC0–24 h(μg h/mL)	104.1 ± 34	79.0 ± 24.5^a	80.9 ± 24.1^a
Frel (%)	–	76.9 ± 13.3	79.7 ± 17.7
HVDt50%Cmax (h)	5.2 ± 2.0	7.6 ± 3.3	12.0 ± 6.3^a
RΔ	2.8 ± 1.1	4.2 ± 1.8	6.5 ± 3.5
C24 h/Cmax (%)	5.9 ± 3.6	26.4 ± 17.3^a	51.0 ± 31.0^a

RΔ: ratio between HVD_t50%C_max of the test formulation and HVD_t50%C_max of an immediate release reference formulation (1.8 h for an ibuprofen suspension).

^aSignificantly different from Ibu-slow® according to a two-way analysis of variance (P < 0.05).

TABLE 2. Pharmacokinetic Parameters Calculated Using Noncompartmental Analysis in Win-nonlin of Rats Dosed with Micronized Particle Extrudate (MPE) Compositions and Crystalline ITZ

Formulation	Tmax (h)	Cmax (ng/mL)	AUC (ng·h/mL)	t1/2 (h)
ITZ-HPMC MPE	4.2 ± 0.3	291 ± 11	2258 ± 146	4.03 ± 0.45
ITZ-PVP MPE	3.5 ± 0	231 ± 11	2049 ± 167	4.7 ± 0.27
Crystalline ITZ	7.5 ± 4.0	107 ± 37	910 ± 542	NA

FIGURE 4. Relationship of polymer molecular weight in the thermal stability of PEO when stored at 60°C, 75% relative humidity, (♦) 1,000,000, (▪) 600,000 and (▴) 200,000.

TABLE 3. Extrusion Stability of PEO 1M and the Influence of PEO 100K on PEO Weight Average Molecular Weight as Measured by Gel Permeation Chromatography, ± SD, n = 3

Formulation (%)				Pre extrusion MW ( × 10^6)	Post extrusion MW ( × 10^6)	% change	Drive current (A)
	CPM	PEO 1M	PEO 100K
A	20	70	10	1.050 ± 0.028	0.958 ± 0.024	−8.8	2.9–3.2
B	20	60	20	0.912 ± 0.023	0.849 ± 0.025	−6.9	2.8–3.2
C	20	40	40	1.135 ± 0.016	1.084 ± 0.018	−4.5	2.4–2.6
				0.084 ± 0.005	0.093 ± 0.008	+10.7

Unprocessed M_W: PEO (1M) M_W = 1.188 ± 0.024.

Zone temperatures: 70°C, 85°C, 100°C, 105°C.

Screw speed: 20 rpm.

FIGURE 5. Influence of TEC concentration and pre-plasticization on the drug release rate of hot-melt extrudate tablets containing 25% w/w 5-ASA. (▴) Formulation pre-plasticized with 12% w/w TEC; (♦) Formulation, not pre-plasticized with TEC; (▪) Formulation, pre-plasticized with 23% TEC.

FIGURE 6. Morphologies of surface and cross-sectional floating HME tablets prepared from formulation containing 10% sodium bicarbonate: (A) Surface 50x, (B) Surface 200x, (C) Cross-sectional 50x, (D) Cross-sectional 200x.

FIGURE 7. CPM release profiles from (A) DC tablets and (B) HME tablets in 900 mL of either (♦) 0.1N HCl, (⋄) pH 4.0 acetate buffer, (▴) pH 4.0 citrate buffer, (Δ) pH 4.0 phosphate buffer, (▪) pH 6.8 phosphate buffer, or (□) pH 7.4 phosphate buffer at 37 ± 0.5°C (USP 27 apparatus 2, 100 rpm). Each point represents the mean ± S.D., n = 3.

FIGURE 8. Glass transition temperatures of HPC/PEO (50:50) hot-melt extruded films containing vitamin E TPGS and three conventional plasticizers (n = 4).

FIGURE 9. (a) Tensile strength and (b) Percent elongation of HPC/PEO 50:50 rRatio hot-melt extruded films containing vitamin E TPGS and three conventional plasticizers (n = 6).

FIGURE 10. Release profiles of clotrimazole from hot-melt extruded Klucel® films as a function of polymer molecular weight.

FIGURE 11. (a) Peak force (adhesive strength) and (b) Work of adhesion of HPC and HPC: HPMC films measured using texture analyzer and rabbit intestinal mucosa as a substrate (n = 5).

FIGURE 12. Influence of tartaric acid on (a) Tensile strength and (b) Percent elongation of hot-melt extruded hydroxypropyl cellulose films.