`Material and Its Effect on Drug Solubility
`
`ABU T. M. SERAJUDDIN~,PAI-CHANG SHEEN, AND MAITHEW A. AUGUSTINE
`
`Received Jul 15, 1985, from the Pharmacy RbD Depament, Revlon Health Care Research, Tuckahoe, NY 10707.
`October 8, lJ85.
`
`Accepted for publication
`
`Abstract 0 The bioavailability of some poorly water-soluble drugs was
`reported to increase due to a change in dosage form from a tablet to a
`solution encapsulated in soft gelatin capsules. However, the objective of
`increasing the bioavailability may be defeated if the drug crystallizes
`from a solution inside the capsule. In this study, a water-insoluble drug
`[a-pentyl-3-(2-quinolinylmethoxy)benzenemethanol; REV 59011 was
`solubilized in both polyethylene glycol 400 (PEG 400) and a 6:l mixture
`of Geluclre 44/14:PEG 400. The solutions were then encapsulated in
`soft elastic gelatin capsules with a fill weight of 700 mg (drug, 125 mg),
`and water migration from the capsule shell into the fill material and its
`effect on the solubility of the drug were investigated. Gelucire 44/14 is a
`mixture of hydrogenated fatty acid esters with a mp of 44°C; PEG 400
`was added to reduce the mp of solution to -36°C for easier encapsula-
`tion. After equilibration of capsules at ambient condition, the amount of
`water in the PEG 400 solution was 6.3%. This reduced the solubility of
`the drug by 45%, resulting in drug crystallization. The solubility de-
`creased exponentially with the increase in water content. The water in
`the encapsulated Ge1ucire:PEG solution was only 1 .l YO, which did not
`affect the solubility significantly.
`
`The advantages of drugs in soft gelatin capsules over
`conventional dosage forms, e.g., tablets, hard gelatin cap-
`sules, solutions, etc., have been reported in the literature.
`The advantages include increased bioavailability,la consum-
`er preference,' better stability,'" easier processibility,1.6 and
`reduced side effects.6 In recent years, there has been a
`renewed interest in soft gelatin capsules after it was shown
`that the bioavailability of digoxin, a poorly water-soluble and
`erratically bioavailable drug, could be increased significant-
`ly by a change in dosage form from a tablet to a soft gelatin
`
`c a p s ~ l e . ~ - ~ In most cases, the primary reason for increased
`bioavailability was that the drug was encapsulated in a
`solubilized form. Following oral intake of capsules, the drug
`dissolves or disperses rapidly in the GI fluid.
`The physicochemical characteristics of soft gelatin cap-
`sules are different from those of other conventional dosage
`forms, and, therefore, special considerations are necessary in
`formulating this dosage form.6J0 Properties of the drug and
`the vehicle, solubility of the drug, processibility of the
`vehicle, compatibility of the drug, the vehicle, and the
`gelatin shell, and stability of these three components after
`encapsulation must be carefully evaluated during formula-
`tion. However, little on the development of bioavailable soft
`gelatin capsule formulations has been reported in the litera-
`ture.
`Due to the high initial water content of the soft gelatin
`capsule shell (>20%),"3 water migrates from the shell to the
`fill material during the drying and subsequent equilibration
`periods.6J0 The objective of increasing the bioavailability of a
`drug by solubilization may be defeated if the drug crystal-
`lizes inside the capsule due to water migration. In this study,
`the effect of water migration on the solubility of a-pentyl-3-
`(2-quinolinylmethyoxy)benzenemethanol(1), a water-insolu-
`ble drug (solubility in water at 37°C -0.002 mg/mL),11 in
`water-miscible vehicles was investigated. Attempts were
`made to minimize water migration by the selection of a
`suitable vehicle. A method of formulating a semisolid solu-
`tion of 1 in a soft gelatin capsule is also described.
`
`Experimental Section
`Chemicals-Compound 1 was synthesized by the Process Chemis-
`try R&D Department of Revlon Health Care Research, Tuckahoe,
`N.Y.I2 Polyethylene glycol (PEG) 400 was purchased from Ruger
`Chemical Co., Irvington, NJ. Gelucire 44/14 was supplied by Gatte-
`fosSe Corp., Hawthorne, NY. This proprietary material is a mixture
`of glyceryl and PEG 1500 esters of fatty acids; the fatty acids are
`produced by the hydrolysis of hydrogenated copra and palm kernel
`oils. It is amphiphilic in nature and, as indicated by the associated
`numbers, has a melting point of 44°C and an HLB value of 14.13
`Gelatin and plasticizers used for encapsulation were supplied by
`R. P. Scherer, Clearwater, FL.
`solubility of 1 in PEG 400 and
`Determination of Solubility-The
`in PEG 400-water mixtures were determined by equilibrating the
`drug with solvents at 20°C for -18 h. A wrist action shaker was used
`to equilibrate the solutions. The solutions were then centrifuged, and
`weighed amounts of supernatant liquids were analyzed spectropho-
`tometrically at 239 nm after suitable dilution with acidified metha-
`nol (1 M HCl:methanol, 1:9).
`In the case of Gelucire 44/14, which is a solid at room temperature,
`a direct determination of solubility was not possible. In this case,
`solutions with varying concentrations of 1 were prepared at 45°C.
`The solutions were then allowed to solidify at room temperature
`(-22°C) and the solid solutions were observed periodically for up to 3
`months under a polarized-light microscope for the presence of any
`drug crystal. The concentration at which a few crystals first ap-
`peared was estimated to be the drug solubility.
`Thermal AnalysisThermal analysis of Gelucire 44/14-based fill
`materials was conducted by using a Du Pont 990 thermal analyzer
`fitted with a differential scanning calorimeter (DSC). The samples
`tions were: sample size, 5 mg; temperature range, from -10°C to
`-80°C; heating rate, lO"C/min; and sensitivity, 0.5 mcal/s/in. (0.2
`mcal/efcm).
`Encapsulation of DrugSolutions of 1 (drug, 125 mg plus vehi-
`cle, 576 mg) were encapsulated in oblong soft gelatin capsules using
`an R. P. Scherer rotary die encapsulation machine. The process is
`essentially similar to that described earlier.1.6JO The solution of 1 in
`PEG 400 was encapsulated at room temperature. The solution in the
`Gelucire 44/14:PEG 400 mixture was filled at 38 f 1°C. Identical
`gelatin shell composition (gelatin, plasticizer and water) was used in
`all capsules. The capsules were equilibrated with 2 0 3 0 % relative
`humidity at room temperature for 7 d by placing them on open trays.
`They were then packaged in high density polyethylene bottles.
`Evaluation of Capsules-The water content of the capsule shell
`and the fill material was determined by Karl Fiecher analysis. To
`determine the water content of the capsule shell, the solution
`adhering to the inner surface of the shell waa scraped out. A
`stability-indicating HPLC method was used to determine the content
`uniformity of the capsules. The possible crystallization of 1 in the fill
`material was studied by using a polarized-light microscope.
`
`Results and Discussion
`Solubility in Polyethylene Glycol 400-Water System-
`The solubility of 1 in PEG 400 and PEG 400-water mixtures
`at 20°C are plotted in Fig. 1(A). Since the solubility of 1
`decreases with an increasing percentage of water, the
`amount of solvent per unit volume of solution differs. There-
`fore, the drug concentration was expressed with respect to a
`constant weight of solvent (milligrams of solute per grams of
`solvent); this is analogous to expressing the concentration in
`molality and has the advantage that a solution may be
`
`62 /Journal of Pharmaceutical Sciences
`Vol. 75, No. 1, January 1986
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`OO22-3549/86/0 1 OO-0062$0 1 . OO/O
`8 1986, American Pharmaceutical Association
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`0001
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`PSG2010
`Catalent Pharma Solutions v. Patheon Softgels
`IPR2018-00421
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`
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`PEG 400 in the vehicle. The drug was dissolved by melting
`the vehicle at -45°C. The concentration of the drug ws
`adjusted such that 575 mg of vehicle contains 125 mg of 1
`(217 mg/g of vehicle). The thermal properties of drug solu-
`tions and vehicles were studied after equilibrating the sam-
`ples at room temperature for -24 h. The results are shown in
`Fig. 2. The DSC thermogram of the fill material of a soft
`gelatin capsule, determined 3 weeks after preparation, is also
`shown in this figure. Since the onsets of melting endotherms
`were not sharp, the melting peaks were compared. The
`samples melted completely within 2°C above the melting
`peak.
`Figure 2 shows that Gelucire 44/14 has its melting peak at
`42°C (thermogram A). This temperature remains unchanged
`when 1 is dissolved in Gelucire 44/14 (thermogram B). The
`melting peak of a 6:l mixture of Gelucire 44/14-PEG 400
`without drug is 41°C (thermogram C). However, when PEG
`400 is incorporated into the drug formulation, the peak
`melting temperature decreases progressively with the in-
`crease in PEG 400 concentration. The thermogram D shows
`that the peak melting temperature of a solution of 1 in a 6:l
`Gelucire 44/14-PEG 400 mixture is 36°C. The reason that 1
`decreased the melting temperature of a Gelucire 44/14-PEG
`400 mixture, but not of Gelucire 44/14 alone, is not clear from
`this study. It is possible that a eutectic mixture was formed
`in the presence of PEG 400. Based on this study, a tempera-
`ture of 38°C was selected for encapsulating the drug solution.
`As indicated by thermogram E, the thermal properties of the
`fill material do not change after encapsulation.
`Soft Gelatin Encapsulation and Effect of Water Migra-
`tion-The drug contents of the capsules containing PEG 400
`and a 6:l Gelucire 44/14-PEG 400 mixture as vehicles were
`found to be 121.9 +: 0.9 mg (SD, n = 10) and 128.0 4 0.6 mg
`(SD, n = lo), respectively, thus showing good content unifor-
`mity. The yields of capsules were 89.5 and 85.48, respective-
`ly, which is satisfactory for batch sizes of 10,000 capsules;
`most of the losses occurred during the initial setting of
`
`A
`
`0
`
`60
`40
`20
`TEMPERATURE, O C
`Figure 2-Differential scanning calorimetry thermograms of various
`formulations of fill material with and without drug. Key: (A) Gelucire
`44/74; (6) drug in Gelucire 44/14 (77.9% w/w); (C) &I mixture of
`Gelucire 44/14-PEG 400; (D) drug in 6: 1 mixture of Gelucire 444 4-
`PEG 400 (17.9% w/w); (E) fill material after encapsulation.
`
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`Journal of Pharmaceutical Sciences / 63
`Vol. 75, No. 1, January 1986
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`10
`40
`Vo WATER IN THE SOLVENT, wlw
`Figure 1-(A) Solubility of a-penfyl-3-(2-quinolinylmetho~)benzene-
`methanol (1) in PEG 400-water cosolvent system at 20 "C. Data points
`at >50% water remain at the baseline. (6) Semilogarithmic plot of
`solubility of 1 in PEG 400-water cosolvent system at 20°C. At <20%
`water, data points at 5% intervals only are shown for the sake of clarify.
`
`50
`
`prepared by accurate weighing. The solubility of 1 in PEG
`400 at 20°C is 250 mg/g of solvent. The solubility decreases
`sharply with the incorporation of water in the system. For
`example, the solubility drops to -100 and -1.5 mg/g of
`solvent in the presence of 10 and 50% water, respectively. A
`semilogarithmic plot of the data in Fig. 1(B) shows a log-
`1inear14 decrease in solubility with the increase in percent-
`age of water in the solvent. Recently, Groves et al.16 also
`observed a similar log-linear decrease in solubility of a poorly
`water-soluble compound in PEG 400-water mixtures, except
`at a low percentage of water (<lo%). The deviation from the
`theoretical relationship at a low concentration of water was
`attributed to a possible chemical interaction between the
`compound and PEG 400. Although a high solubility of 1 in
`PEG 400 indicates a high solute-solvent affinity, no devi-
`ation from the theoretical relationship is observed.
`Solubility in Gelucire 44/14 and Gelucire 44/14-Polyeth-
`ylene Glycol 400 Mixture-The
`solubility of 1 in Gelucire
`44/14 at room temperature (-22'0, as determined by the
`microscopic method, was found to be 200 mg/g of vehicle; a
`progressively greater number of 1 crystals were observed
`with the increase in drug concentration above this level. No
`crystals of 1 were, however, observed at room temperature
`for at least 3 months when 217 mg of the drug was dissolved
`per gram of a 6: 1 mixture of Gelucire 44/14 and PEG 400. The
`latter concentration of drug was used in the fill material to
`maximize the amount of drug per capsule. Since the solubili-
`ties of 1 in Gelucire 44/14 and PEG 400 at 20-22°C were
`-200 and 250 mg/g, respectively, a concentration of 217 mglg
`of a 6:l mixture of Gelucire 44/14 and PEG 400 was consid-
`ered to be in the region of saturation solubility.
`Reduction of Melting Point of Gelucire 44/14-Gelucire
`44/14 has a melting point of 44°C (range: 4246°C). Since the
`turing is 37-4O0C:Jo 1 dissolved in a melt of Gelucire 44/14
`could not be encapsulated due to its high melting point
`relative to the sealing temperature. The melting point at the
`drug solution was, therefore, reduced by the incorporation of
`
`0002
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`machines. Although the Gelucire 44114 based formulation
`was encapsulated at or near the temperature necessary to
`seal the gelatin shells, there was no significant loss of
`capsules due to defective sealing.
`The water content of fill materials and capsule shells was
`analyzed 3-4 weeks after preparing the capsules. When a
`solution of 1 in PEG 400 was used, the amount of water in the
`fill material was 6.4 2 0.1% of the initial fill weight. In
`contrast, the water content of the fill material where Gelu-
`cire 44114-PEG 400 was used to dissolve the drug was 1.1 2
`0% of the fill weight. The water contents of the capsule shells
`were 9.6 t 0.2 and 5.6 t 0.1%, respectively.
`The initial microscopic analysis of the contents of soft
`gelatin capsules for the presence of 1 crystals was made 3-4
`weeks after the preparation of the capsules. The capsules,
`after initial equilibration at 20-30% relative humidity for 1
`week, were stored at 22”C, protected from moisture. Gross
`crystallization of 1 was observed in soft gelatin capsules
`containing only PEG 400 as a vehicle. Initial concentration of
`the 1 solution inside the capsule was 17.9% wlw, which is
`below its saturation limit in PEG 400 (20% wlw at 20°C). The
`observed crystallization was, therefore, due to a lowering of
`solubility by the migration of water to the fill material. Only
`-80 mg of 1 remained in solution inside the capsule, which is
`in general agreement with Fig. 1. For comparison, a 17.9%
`wlw solution of 1 in PEG 400 was filled manually in hard
`gelatin capsules or glass vials, and stored under identical
`environmental conditions. No crystallization of drug was
`observed during 3 months of observation. Since, unlike a
`solution in PEG 400, the migration of water into the drug
`solution in Gelucire 44/14-PEG 400 was minimal, no crystal-
`lization of 1 was observed in this fill material for 3 months.
`The gelatin mass used to prepare soft gelatin capsule shells
`may contain 30-40% water.’ During drying and subsequent
`equilibration of capsules, the water may partially migrate
`into the fill material. The extent of such a migration of water
`may depend on the nature of the solvent or matrix used in the
`fill material. The lower water content of the fill material
`containing a mixture of Gelucire 44/14-PEG 400 as com-
`pared to PEG 400 alone may be related to the lower hydro-
`philicity of Gelucire 44/14 compared to that of PEG 400
`(HLB: 14 versus -20) and the low diffusion coefficient of
`water in the semisolid matrix.
`The water contents determined in the present study are
`essentially the equilibrium values. There was no significant
`change in the amount and shell-to-fill ratio of water in
`Gelucire 44/14 based capsules when stored in closed 45-mL
`high-density polyethylene bottles (20 capsuleshottle) under
`varying conditions (@C, 25”C, and 35°C) for an additional 3
`months. Due to gross crystallization of the drug, the stability
`of PEG 400 based capsules was not studied for an extended
`period of time.
`
`Another major difference between PEG 400 and Gelucire
`44/14-PEG 400 was in the particle sizes of drugs crystalliz-
`ing out of these vehicles. The majority of crystals in the PEG
`400 based formulation were 500-1000 pm. On the other
`hand, all crystals observed in the formulation containing the
`Gelucire 44114-PEG 400 mixture by reducing its tempera-
`ture to -4°C or by increasing the initial concentration of
`drug were <15 pm. This is possibly due to a difference in
`crystal growth in liquid and semisolid vehicles.
`One major limitation of soft gelatin capsules is the amount
`of drug that may be encapsulated as a solution. This is of
`particular concern if a high dose of drug is necessary.
`Sometimes the required amount of drug may not be solubi-
`lized in the best suitable solvent. The results of the present
`investigation show that this situation might be further
`complicated by a lowering of solubility due to water migra-
`tion. The migration of water, and thus the crystallization of
`1, can be minimized by changing, among other possible
`factors, the vehicle.
`In conclusion, the results of the present investigation
`highlight the importance of a critical evaluation of shell-to-
`fill water migration in formulating soR gelatin capsules.
`
`References and Notes
`1. Seager, H. Pharm. Tech. 1985,9(9), 84-104.
`2. Batemann, N.; Uccellini, D. A. J. Pharm. Pharmacol. 1984,36,
`461-464.
`3. Berry, I. R. Drug Cosm. Znd. 1983,133,32.
`4. Delane , R. Pharm. Exec. 1982,2, 3438.
`5. Ebert, 64. R. Pharm. Tech. 1977,1(5), 44-50.
`6. Caldwell, L.; Cargill, R.; Ebert, W. R.; Windheuser, J. J. Pharm.
`Tech. 1979,3(7), 52-56.
`7. Mallis, G. I.; Schmidt, D. H.; Lindenbaum, J. Clin. Pharmacol.
`Ther. 1975,18, 761-768.
`8. Marcus, F. E.; Dickerson, J.; Pippin, S.; Stafford, M.; Bressler, R.
`Clin. Pharmcol. Ther. 1976,20, 253-259.
`9. Johnson, B. F.; Bye, C.; Jones, G.; Sabey, G. A. Clin. Pharmacol.
`Ther. 1976,19,746-751.
`10. Stanley, J. P. in “The Theory and Practice of Industrial Pharma-
`7” ebiger: Philadel hia, 1976; p 404-420.
`; Lachman, L.; Lieberman, H. A.; Kanig, J. L., Eds.; Lea &
`11. Serajuddin, A. T.R.; Sheen, F. C:; Bernstein, D. F.; Mufson, D.;
`Augustine, M. A. J. Pharm. Sci. in press.
`12. Compound 1 is also known as REV 5901.
`13. Wagmaire, L.; Glas, B. “Gelucire”, technical literature, No. 74,
`Gattefossb Co.: 1981; pp 3-8.
`14. Yalkowsky, S. H.; Flynn, G. L.; Amidon, G. L. J . Phurm. Sci.
`1972,61, 983-984.
`15. Groves, M. J.; Bassett, B.; Sheth, V. J. Pharm. Pharmacol. 1984,
`36.799-802.
`
`Acknowledgments
`“he authors thank R. P. Scherer North America, Clearwater, FL,
`for the use of its facilities in encapsulating soft gelatin capsules. The
`assistance of Ms. E. Eger in the preparation of this manuscript is
`gratefully acknowledged.
`
`64 / Journal of Pharmaceutical Sciences
`Vol. 75, No. 1, January 1986
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