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Dissolution Rate Studies of Compression-Molded Units Made From Hydroxypropyl Cellulose Films

L. A. GRABOWSKI', J. v. BONDI, AND R. J. HARWOOD' Received April 28, 1983, from Pharmaceutical Research, Merck Sharp & Dohme Research Laboratories, West Point, PA 19486. Accepted for publication January 16, 1985. Present address: 'William H. Rorer, Inc., Fort Washington, PA 19034.

Abstract 0 Hydroxypropyl cellulose films were prepared by compression molding of three different lots of hydroxypropyl cellulose powder at 149'C, 188'C, and 232°C. Rectangular piec-es were cut from these films and viscosity average molecular weight (MJ, degree of orientation, and rate-of dissolution were measured. The viscosity average molecular weight (M,) decreased with increasing processing temperature, while, as expected, the dissolution rate increased. Orientation in the thermoformed units was also evaluated. Correlation of these data with the M, values suggests that orientation has some controlling influence on the dissolu- tion rate. Because the samples possessing the least orientatJon were molded at the highest temperature, they also had the lowest M, due to thermal degradation. Therefore, the effects of molecular weight were not fully separated from orientation effects with regard to control over the dissolution rate.

Physicochemical attributes of polymeric systems such as orientation, molecular weight, and crystallinity are often af- fected by the processing techniques used to convert a thermo- plastic material into an article of use. For example, thermal, oxidative, and/or shear degradation may affect the molecular weight of a long-chain molecule as a consequence of hot-melt extrusion. Additionally, when polymers are heated and stretched during a thermoforming operation such as extrusion molding, orientation can be imparted to the material as a result of polymer flow. If cooling occurs prior to removal of the stress, molecular orientation is generally retained in the processed unit. Other processing methods such as blow molding, calen- dering, or compression molding apply similar mechanical stress (or strain) to a polymeric material. Compression molding, which we have studied in this investigation, may impose ther- mal and/or oxidative stress on a polymer, but orientation effects due to flow are minimal and orientation would be expected to be more planar for compression-molded sheets, whereas the orientation would be uniaxial for an extruded filament or a drawn sheet.

In this study, hydroxypropyl cellulose films were prepared by compression molding three lots of hydroxypropyl cellulose HF powder at three different molding temperatures. Rectangular pieces were then cut from these films and measurements were made of the viscosity average molecular weight (MY); indirect measurements of the amount of amorphous orientation in the films were also made. Finally, the rate of dissolution-of the polymer (in water) was measured to determine if M, and orientation, which are affected by the processing conditions used, would affect the dissolution behavior of compression- molded hydroxypropyl cellulose.

Experimental Section Materials-Three different lots of hydroxypropyl cellulose

(Klucel HF; Hercules, Wilmington, DE), referred to as A (lot 3006), B (lot 3957), and C (lot 1062), were used as received.

Preparation of Compression-Molded Films-Hydrox- ypropyl cellulose powder samples were dried overnight a t 35"C,

540 /Journal of Pharmaceutical Sciences Vol. 74, No. 5, May 1985

under reduced pressure. Eight grams of the dried powder was placed in the center of a 15.2 x 15.2-cm Teflon-coated brass plate; a similar size stainless-steel shim (0.5-0.7-mm thickness) with a 10.2 x 10.2-cm open-square center portion was placed around the powder. A second Teflon-coated brass plate identi- cal to the first was placed on top of the powder. This assembly was then transferred to the bottom platen of a hydraulic press (model C; Fred S. Carver, Menomonee Falls, WI) equipped with heating and cooling platens which had been preheated to 149"C, 188"C, or 232°C. The top and bottom platens were brought together under a force of 4500-6000 kg for 1 min. The heating element was then unplugged, and cold water was cir- culated through the platens for at least 3 min to cool the sample. The pressure was released and the plate assembly was removed from the press. The film was removed and cut into rectangular units with a specially designed punch (Hoggson and Pettis Manufacturing Co., Wallingford, CT). Length and width of these pieces were -6.2 and 1.7 mm, respectively. Each unit weighed -5 mg. The temperatures chosen for this experi- ment were based on differential scanning calorimetry (DSC) observations of hydroxypropyl cellulose (DSC 1-B; Perkin- Elmer, Norwalk, CT). Thermal changes observed by DSC usu- ally begin at -149°C. Samuels' has reported that the last crystals of hydroxypropyl cellulose (which is a partially crys- talline material) melt a t 234°C. The intermediate temperature, 188"C, had been used in previous melt-extrusion experiments.

Measurement of In t r ins ic Viscosity a n d Determina- tion of Viscosity Average Molecular Weight-Samples of the hydroxypropyl cellulose units were dried at 30-35°C for 16 h. Five solutions, each of a different concentration (range, 0.03- 0.1% w/v) were prepared in ethano1:water (l:l), which was prepared by adding 500 mL of ethanol (ethyl alcohol USP, anhydrous; U S . Industrial Chemicals Co.) to 500 mL of dis- tilled water and mixing thoroughly. Polymer solutions were shaken for a minimum of 16 h on an oscillating bed shaker and then equilibrated to 25 rf: 1°C in a water bath before being introduced into a Ubbelobde No. 1 viscometer (Arthur H. Thomas Co., Philadelphia, PA). Solutions were introduced into the viscometer through a filtering cone constructed from 100- mesh stainless-steel screen which was placed in an -5-cm (2- in.) diameter funnel. The flow time of the solution through the viscometer was measured with a stopwatch and recorded to the nearest 0.1 s; pure solvent (ethanokwater) was similarly tested. The relative viscosity (orel) of each solution was obtained by dividing the flow time of the sample solution by the flow time of the solvent. Intrinsic viscosity was then calculated from the relative viscosity data using the Martin

where qsp = orel - 1, [v ] is the intrinsic viscosity, and C is the concentration of hydroxypropyl cellulose (g/lOO mL). The plot of log (ogp/C) versus C gives a straight line whose y-intercept is equal to the intrinsic viscosity. Regression analysis was used to determine the intrinsic viscosity from the experimental data.

0022-3549/85/0500-0540$01.00/0 0 1985, American Pharmaceutical Association

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or the HRR. This relationship is shown below: The average degree of polymerization (m,) was then ob- tained using the equation:

[77] = 0.0095 DP,0.9 which relates m, to intrinsic viscosity in a method analogous to that employed in the Mark-Houwink e q ~ a t i o n : ~ - ~

(3) Equation 2 was recommended' for the determination of m,, where the constants 0.0095 and 0.9 were determined at Hercules Inc., using light scattering and ultracentrifugation sedimenta- tion methods in conjunction with relative viscosity.

Finally, the viscosity =rage molecular weight (mi,) was obtained by multiplying DP, by the molecular weight of the repeat unit of the batch of hydroxypropyl cellulose being stud- ied. The molar substitution (M.S.) value supplied by the man- ufacturer was used to calculate the molecular we@t of the monomer unit. It should be noted that the use of DP, in the calculation resultsin values classified 5s the weight average molecular weight (Mw). However, M, = M, when the exponent a of eq. 3 is equal to unity. Since a for hydroxpropyl cellulose is equal to 0.9, the values designzted here as M, are very close to and only slightly lower than M,.

Determination of the Relative Degree of Orienta- tion-The heat relaxation ratio (HRR) of the rectangular hydroxypropyl cellulose units was obtained by measuring length, width, and thickness of the units to the nearest 0.01 mm with a Vernier caliper, placing the units individually into open cups of a differential scanning calorimeter, heating them for 6 min at 212"C, cooling to room temperature, and measuring them again. Six replicate determinations were made for each sample material.

The relationship between the pre- and postheating dimen- sions of the units provided an index of orientation within the polymer sample which was termed the "heat relaxation ratio"

(4)

where L, W, and T are the unit length, width, and thickness after heating, respectively, and Lo, Wo, and To are the initial unit length, width, and thickness, respectively. The relationship between length and thickness as well as that between width and thickness was considered; the average of these two values was taken as the index of orientation in these samples. Systems containing lower orientation should have an HRR approaching unity, while deviations from one can be related to a more highly oriented system.

Measurements of the swelling of the material in two dimen- sions in a nonsolvent were employed to determine the aniso- tropy ratio (AR). The solvent system consisted of 10% metha- no1:petroleum ether (v:v) which was prepared by transferring 10 mL of methanol (Fisher Scientific Co., Fair Lawn, NJ) into a 100-mL volumetric flask and filling to the mark with reagent- grade petroleum ether (bp 35-60°C; Mallinckrodt, St. Louis, MO). This solution was prepared immediately before use. Rec- tangular pieces punched from the compression-molded sheets were measured with a Vernier caliper to the nearest 0.01 mm, and length and width were recorded. Six determinations were made for each sample batch. Six standard size quartz cuvettes (all clear, no frosted sides) were placed upright in a 6 cm x 12- cm diameter crystallization dish, and each was filled with -3.5 mL of the methano1:petroleum ether solution. The remainder of the 100 mL of solution was poured into the dish, and one rectangular unit was carefully dropped into the solvent in each cuvette. The dish was covered with a large watch glass and the samples were examined after 2.5 h. Without removing the

I l l 1 I l l / 0 0.02 0.04 0.06 0.08 0.10 0.12 0.14

Concentration, s/100 rnL

Figure 1-Graphic representation of the Martin equation [log (qsp/C) = log 171 + k[q]C] using hydroxypropyl cellulose lot C. Key: (0) 188°C; (0) 232°C.

1 49 188 232 Temperature, OC

Figure 2-Viscosity average molecular weight (MJ of hydroxypropyl cellulose in compression-molded films versus the compression molding temperature. Key: (0) lot A; (A) lot 6; (0) lot C.

Table I-Dissolution Profiles and Other Physicochemical Data for Compression-Molded Films Prepared from Three Different Lots of Hvdroxypropyl Cellulose (HPC) at Three Different Processing Temperatures

H ydroxy propyl Molar Compression Molding HPC Dissolved, mg Cellulose Substitution Temperature, O c 2 h 4 h 6 h 7 h '

A 3.7 149 0.73 1.80 2.93 3.47 9.93 X lo5 188 0.88 1.85 3.18 3.82 7.81 X lo5 232 1.07 2.57 4.42 4.80 7.21 X lo5

B 4.23 149 0.83 1.95 3.03 3.62 9.73 X lo5 188 1.22 2.98 4.63 5.34 8.01 X lo5 232 1.29 2.76 4.23 4.98 7.56 X lo5

C 3.7 149 0.90 1.95 2.92 3.37 9.33 X lo5 188 0.84 1.93 3.16 3.81 9.21 X lo5 232 0.70 2.48 3.48 4.02 8.99 X lo5

Heat Relaxation Ratio (HRR)b

0.329 0.384 0.721 0.329 0.386 0.573 0.356 0.377 0.648

0.308 0.359 1.09 0.351 0.355 0.978 0.344 0.31 5 0.916

a M - - viscosity average molecular weight. ' HRR = average of two determinations, (L/T)/(b/To) and (W/l)/(Wo/To). AR = (L/W)/ (b/Wo).

Journal of Pharmaceutical Sciences / 541 Vol. 74, No. 5, May 1985

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swollen pellets from the cuvettes, the new dimensions were measured with the Vernier caliper.

This method of measuring the degree of orientation of ther- moformed polymer samples involves swelling the units with a nonsolvent that causes the polymer to swell but not dissolve. As the nonsolvent permeates the network of oriented polymer molecules, the molecules will relax. The degree of orientation is defined as the anisotropy ratio (AR) and can be calculated using the following relationship:

where L and W are the solvent-treated unit length and width. Isotropic systems (i.e., those containing no orientation) will have an AR approaching unity. The advantage of solvent relaxation over heat relaxation is that thermal degradation which may occur during heating is avoided.

Measurement of the Rate of Dissolution-A USP/NF rotating-basket dissolution apparatus' was used. The dissolu- tion vessels consisted of modified centrifuge bottles (60 mm 0.d. x 142 mm; Fisher Scientific Co.) which were cut and flanged to resemble the shape of the 1-L USP vessel but having final dimensions of 100 mm x 55-60 mm i.d. and a capacity of -150 mL. Three compression-molded units were weighed in- dividually to the nearest 0.01 mg. Additional samples from the batch were analyzed for moisture content via the Karl Fischer method (Aquatest I1 Karl Fischer Titrator; Photovolt Corp., New York, NY). Exactly 120 mL of distilled water was added to each vessel. The empty baskets were lowered into the dis- solution pot, positioned 2 cm from the bottom and stirred at 100 rpm for 10 min before a 2.0-mL aliquot (control) was taken. The volume was replaced with 2.0 mL of distilled water. The baskets were removed momentarily so that one previously weighed sample could be placed into each basket; they were then lowered into the dissolution vessels and agitated at 100 rpm. After 2 ,4 ,6 and 7 h, 2.0-mL aliquots of the medium were transferred to separate clean test tubes for subsequent analysis for the quantitative determination of hydroxypropyl cellulose. After each sampling, 2.0 mL of distilled water was added to each vessel to maintain a constant volume. The temperature throughout the entire test was maintained at 37°C.

1

q 3 4.0-

ai a, a

Figure 3-Dissolution profiles for $ compression-molded films prepared from 4 3.0 - three different lots of hydroxypropyl cel- = lulose at three different processing tern- 0" peratures. Key: (0) 749OC; Q) 788OC; (A) 232 OC.

-

g 2.0 - i! f

>r

'0

LOT A

An autoanalyzer (Technicon Instruments Corp., Chauncey, NY) equipped with colorimeter, heated oil bath (95-97"C), and appropriate plastic cups, tubing, and glass fittings was utilized for the quantitation of hydroxypropyl cellulose via the colori- metric anthrone assay." The autoanalyzer pump was first purged for 15 min with Brij solution [0.5 mL of Brij (Technicon reference T-21-0110-5) dissolved in 1000 mL of distilled water] in the reagent lines, then for an additional 15 min with an- throne reagent [1.5 g of anthrone (Fisher Scientific Co.) is dissolved in 200 mL of concentrated sulfuric acid (J. T. Baker Chemical Co.) in a 1000-mL volumetric flask; after cooling, 330 mL of glacial acetic acid (Mallinckrodt) is carefully added, the solution is cooled again, and concentrated sulfuric acid is added again until the total volume is about 995 mL; 2 mL of Brij is then added and the flask filled to the mark with concentrated sulfuric acid]. All glassware was rinsed with concentrated sul- furic acid and then with distilled water and dried to prevent the reaction of anthrone reagent with trace contaminants.

Standards of hydroxypropyl cellulose in distilled water were run in duplicate in increasing order of strength, followed by a blank of distilled water, and finally the samples to be tested. Calculation of the results was by comparison of sample absorb- ance to standard absorbance at 620 nm via a standard curve of absorbance versus concentration established by the absorbance readings of the standards. Interpolation of sample concentra- tion from the standard curve, corrections for removal of hy- droxypropyl cellulose at each sample point and subsequent replacement of solvent, and dilution factors inherent in the method were calculated. The moisture content of the pellets was corrected by entering the pellet weights on an anhydrous basis.

Results and Discussion Figure 1 shows data typical of the intrinsic viscosity deter-

minations, obtained using lot C. As seen in the figure, the plot of log (vSp/C) versus C resulted in a straight line. Regression analysis was used to extrapolate to the y-intercept and thus determine the intrinsic viscosity from the experimental data. Table I shows the viscosity average molecular weights which were observed in the hydroxypropyl cellulose material after compression molding each lot at 149"C, 188"C, or 232°C. It is apparent that heat stress does cause molecular weight degra-

2 4 6 7 Hours

LOT B

P

- 2 4 6 7

Hours

LOT C

4

- 2 4 6 7

Hours

542 /Journal of Pharmaceutical Sciences Vol. 74, No. 5, May 1985

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5 -

4-

3 -

2-

1-

0 'I 6 7 8 9 1 0 1 1

M, ( X 10-5)

Figure 4-Amount of hydroxypropyl cellulose dissolved (mg) versus viscosity average molecular weight (&). Key: (0) 2 h, slope = -0.155 x

r = -0,747799; (A) 4 h, slope = -0.292 x lo-', r = -0.656340; 0 6 h, slope = 0.547 x r = -0.802835.

dation in this material. Moreover, lot C appears to be more resistant to thermal degradation than the other two lots (Fig. 2).

The dissolution profiles, the viscosity average molecular weights, the heat relaxation ratios, and the anisotropy ratios of the thermoformed hydroxypropyl cellulose pieces studied in this experiment are shown in Table I. The dissolution rate profiles are shown in Fig. 3. The relationship between process- ing temperature and dissolution rate is apparent from these data; generally, those units molded a t 232°C dissolved a t the most rapid rate and those processed at 149°C dissolved at the slowest rate.

As discussed, however, increasing the processing temperatKe causes a decrease in the M, of the material. Examining the M, data in Table I, one can see immediately the degradative effegs on the hydroxypropyl cellulose material by the decrease in M, as the processing temperature is raised from 149°C to 188°C to 232°C. Therefore, the correlation betwee? the amount of hy- droxypropyl cellulose dissolved and the M, of the polymer in the units tested was examined (Fig. 4). A trend is apparent: a relationship exists between the amount of hydroxypropyl cel- lulose dissolved and the Mv of the initial polymer sample and is independent of the sampling time. Figure 4 shows the data obtained at 2,4 , and 6 h. Regression analysis was used to obtain the linear fit of the data as shown in the plot.

Experiments were also carried out to examine molecular orientation in these compression-molded units. When amor- phous polymeric systems are displaced from a randomly coiled configuration, e.g., by the processing methods described previ- ously, they are considered oriented. Such orientation results in anisotropy in a number of physical properties of the polymer, such that these properties vary in value with the direction in or along which the measurement of the property is made. Optical, mechanical, or sonic properties are examples of those parameters which may be affected. An indirect measure of the amount of amorphous orientation present within a thermo- formed polymer sample can be obtained by heating the sample above the softening temperature of the material to allow the oriented molecules to relax and comparing the dimensions of the unit before and after heating. In these experiments, we measured the length, width, and thickness of the units before and after heating for 6 min at 212°C in open cups on the DSC. The temperature was slightly greater than the 188°C processing temperature previously shown to be suitable for melt extrusion of this grade of hydroxypropyl cellulose. We have used these measurements of dimensional changes in our samples to deter- mine anisotropy. Additionally, we employed a solvent-uptake

I I I I I I 0.3 0.4 0.5 0.6 0.7 0.8

HRR

Figure 5-Amount of hydroxypropyl cellulose dissolved (mg) versus heat relaxation ratio (HRR). Key: (0) 2 h, slope = 0.3784, r = 0.273066; (A) 4 h, slope = 1.7690, r = 0.595530; (0) 6 h, slope = 3.8605, r = 0.452372.

method to evaluate orientation in these samples, and the nu- merical results were virtually identical. The data are shown in Table I and Fig. 5 .

As seen in Table I, all three lots of hydroxypropyl cellulose, when molded at 149°C or 188"C, show remarkably similar HRR values (-0.3-0.4). Differences are seen only at the 232°C mold- ing condition where values of 0.6-0.7 are obtained. Since more thermal degradation also takes place during molding at this temperature, orientation may be minimized due to greater mobility and shorter relaxation times among the smaller mol- ecules. Referring to the data for lots A and C, it is apparent that for pieces molded at the two lower temperatures, which are quite similar in HRR, the amounts of hydroxypropyl cel- lulose dissolved are also quite similar despite the fact that the M, values range from 7.8 X lo6 to 9.9 x lo5. These data support the suggestion that orientation has some controlling influence on the dissolution rate. This is not surprising since permeability and sorption have been known to be influenced by orientation in semicrystalline polymeric materials." The graphical pres- entation of the data (Fig. 5 ) illustrates the relationship between the HRR values and milligrams of hydroxypropyl cellulose dissolved. This plot would suggest that the orientation exerts little control over dissolution in the first 2 h (i.e., the slope of the line approaches zero). At the 4- and 6-h points, however, the more highly oriented samples (lower HRR) dissolved more slowly than those with less orientation; thus, a positive slope is obtained, indicating a more rapid rate of dissolution for the less oriented samples. Interestingly, those samples with least orientation were molded a t 232°C and, thus, were subject to the most thermg stress; each sample, after molding at 232"C, had the lowest M, and the least orientation as compared with the other samples of the same lot of hydroxypropyl cellulose. The effects of molecular weight were thus not fully separated from orientation effects with regard to control over the disso- lution rate. The mechanism of dissolution of hydroxypropyl cellulose would seem to be dependent on both parameters concurrently.

The results of this study indicated that the dissolution be- havior of compression-molded hydroxypropyl cellulose units is dependent on both the molecular weight of t_he polymer and its orientation in the matrix. Moreover, since M, and orientation are affected by temperature, it may be possible to utilize this manufacturing variable to alter the solubility characteristics of a product in a predictable manner. The dissolution test used was found to be sensitive to the changes that occurred in hydroxypropyl cellulose caused by processing, and it thus pro- vides a convenient means of monitoring these changes.

Journal of Pharmaceutical Sciences / 543 Vol. 74, No. 5, May 1985

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References and Notes 1. Samuels, R. J. Appl. J. Polym. Sci. 1969 , 7, 1197-1258. 2. Collins, E. A.; Bares, J.; Billmeyer, F. W. “Experiments in Polymer

Science”; Wiley-Interscience: New York, 1973. 3. Wirick, M. G.; Waldman, M. H. J . Appl. Polym. Sci. 1970 , 14,

579. 4. Wirick, M. G. J. Appl. Polym. Sci. 1968 , 6, 1705-1716. 5. Marx-Figini, M. in “Cellulose and Other Natural Polymer Sys-

tems”; Brown, R. M., Jr., Ed.; Plenum Press: New York, 1982; pp

6. Quackenbos, H. M. J. Appl. Polym. Sci. 1980,25,1435-1442. 7. Gelman, R. A. J. Appl. Polym. Sci. 1982 ,27 , 2957-2964. 8. Hercules Incorporated, Research Center (Method K45-5b), person-

243-271.

nal communication.

9. “US. Pharmacopeia XX/National Formulary XV”; U S . Pharma-

10. Morris, D. L. Science 1948 , 107, 254-255. 11. Mohajer, Y.; Wilkes, G. L.; McGrath, J. E. J. Appl. Polym. Sci.

copeial Convention: Rockville, MD, 1980; p 959.

1 9 8 1 I 26,2827-2839.

Acknowledgments Presented before the Industrial Pharmaceutical Technology Section

a t the 31st National Meeting of the American Pharmaceutical Associ- ation Academy of Pharmaceutical Sciences, Orlando, FL, November 1981. The authors wish to express their sincere gratitude to Dr. Garth L. Wilkes for his guidance during the course of these experiments and his assistance in the preparation of the manuscript.

544 /Journal of Pharmaceutical Sciences Vol. 74, No. 5, May 1985

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