`Dissolution Rates for a Series of Drugs
`
`FOO SONG HOM and JOHN J. MISKEL
`
`The study illustrates the influence oral dosage form
`Abstract
`design has on dissolution rates for drugs from different chemical
`and pharmacological classes. Comparative data demonstrate that
`relatively insoluble drugs, when formulated in soft elastic capsules,
`are released faster than from commercially available tablets. Faster
`dissolution from soft elastic capsules is believed to be due to the
`more rapid dispersion of the active ingredients. Rapid dispersion of
`medicaments is enhanced by the use of solubilizers and/or sur-
`factants in the formulation design. Soft elastic capsules are recom-
`mended for the formulation of low-dose medications, of relatively
`insoluble drugs, and of drugs where early high-blood level of the
`drug is indicated.
`Keyphrases 0 Oral dosage form design effectdissolution rates 0
`Capsules, soft elastic, tabletsarug release-rate comparison Ro-
`tating-bottle apparatus4issolution testing 0 UV spectrophotom-
`etry-analysis
`
`In recent years, numerous scientists have demon-
`strated the direct relationship between proper formula-
`tion of a dosage form and the production of a clinically
`effective drug product. Many correlations have been
`established between formulation design and therapeutic
`activity, reporting the interrelation of particle size, dis-
`solution, and absorption. In a review, Nelson (1) indi-
`cated that the rate of gastrointestinal absorption of a
`drug is often a function of the time needed for the drug
`to dissolve in the fluid at the site of absorption. He
`pointed out that, in general, the availability for absorp-
`tion decreases in the order: solution > suspension >
`powder-filled capsule > compressed tablet > coated
`tablet. However, changes in this order may occur for
`various reasons, but they are exceptions. Tannenbaum
`et al. (2) demonstrated that in some cases, through the
`use of modern pharmaceutical techniques, it is possible
`to produce a tablet that results in greater drug absorp-
`tion than a powder-filled capsule. Wagner et al. (3), in
`their study on the effect of dosage form on serum levels
`of indoxole, observed that the serum level response de-
`
`100
`
`80
`0
`
`w > d 60
`v) z
`0 40
`
`4
`
`12
`
`1
`28
`20
`MINUTES
`rates of hydrocortisone capsule and tablet
`Figure I-Dissolution
`in simulated gastric fluid T.S. Key: 0, so# elastic capsule; and O,
`Tablet A .
`
`I
`36
`
`I
`44
`
`I
`52
`
`I
`60
`
`100
`
`80
`
`0 w > $ 6o
`
`E
`0 4 0
`b?
`
`20
`
`4 12 20
`
`36
`28
`MINUTES
`Figure 2-Dissolution rates of ethinyl estradiol capsule and tablets
`in simulated gastric fluid T.S. Key: 0 , soft elastic capsule; 0,
`Tablet A ; and@, Tabfet B.
`
`44
`
`52
`
`60
`
`creases in the order: emulsion (Lipomul-Oral) % soft
`gelatin capsule > aqueous suspension > powder-filled
`capsule. Aguiar et al. (4) studied and correlated the
`effects of deaggregation or dispersion, dissolution, and
`in vitro gut-permeation rates on the chloramphenicol
`availability from four commercial lots of capsules.
`Glazko et al. ( 5 ) observed different absorption rates
`from capsules containing identical amounts of chloram-
`phenicol from different manufacturers. Similarly, Brice
`and Hammer (6) observed significant differences in
`serum antibiotic levels obtained from 16 commercially
`available lots of oxytetracycline capsules distributed by
`13 different suppliers.
`The present work is a study of the influence of soft
`elastic capsule and tablet dosage forms on dissolution
`rates for a series of chemically and pharmacologically
`different drugs. While it will be agreed that in vitro disso-
`lution rate data do not necessarily reflect in vivo absorp-
`tion and availability, sufficient correlation exists to
`justify the use of this technique to measure potential
`dosage form efficiency (7-12). The rotating-bottle
`method (13-15) is used to compare the dissolution rates
`of soft elastic capsules and tablets.
`
`r-
`
`loot
`
`4
`
`12
`
`36
`28
`20
`MINUTES
`Figure 3-Dissolution rates of diethylstilbestrol capsule and tablets
`in simulated gastric fluid T.S. Key: 0, soft elastic capsule; 0,
`Tablet A ; and@, Tablet B.
`
`44
`
`52
`
`60
`
`Vol. 59, No. 6, June 1970 [7 827
`MYLAN EXHIBIT 1034
`
`
`
`t
`
`100
`
`80 n
`W > 6 60
`cn
`“,
`n 40 s
`20
`
`LL 3.0 n
`
`4
`
`8
`
`16
`12
`MINUTES
`Figure 4-Dissolution rates of phenobarbital capsuleand tablet in sim-
`ulated gastric fluid T.S. Key: @, soft elastic capsule; and 0, Tablet A .
`
`20
`
`24
`
`28
`
`-
`
`80
`n
`W > 6 6 0 -
`m cn
`4 0 - s
`
`2ot Y A ,
`
`I 4 , I
`8
`4
`
`I
`I
`16
`12
`MINUTES
`Figure 7-Dissolution
`rates of bishydroxycoumarin capsule and
`tablet in simulated gastric fluid T.S. Key: @, soft elastic capsule;
`and 0, Tablet A .
`
`I
`20
`
`1
`24
`
`I
`28
`
`the purpose of this study the drugs chosen
`Products Tested-For
`represent a number of chemical and pharmacological classes. The
`soft elastic capsules were manufactured using the continuous rotary
`die process. The drugs, where possible, were dissolved in poly-
`ethylene glycol 400 USP or suspended in various polyols with 1-
`of a nonionic surfactant. In some cases the dispersion vehicle
`3
`was a nonionic surfactant or mixture of nonionic surfactants. Com-
`mercial capsules and tablets were purchased on the open market.
`These include “brand name” drugs and their generic counterparts.
`rotating-bottle apparatus (1 3-1 5) was used for the
`Method-The
`dissolution tests in the following manner. Into each of the bottles
`was placed 50 ml. of simulated gastric fluid T.S. (without pepsin),
`and the bottles were allowed to come to temperature equilibrium in
`a water bath at 37.5 -I: 0.1 O. One tablet or capsule was added to each
`bottle and rotation begun at about 40 r.p.m. At suitable time in-
`tervals, a bottle was removed and the contents filtered immediately
`through a 0.22-1.1 Millipore filter in a microsyringe filter holder.’
`An aliquot of the clear filtrate was diluted and analyzed by appro-
`priate USP (16) methods of colorimetry or spectrophotometry.
`Ethinyl estradiol was analyzed by a special colorimetric method (17).
`A technique similar to the one published by Burns et al. (18) was
`used to analyze phenylbutazone (A = 265 mp, 0.1 N NaOH).
`Similarly the method of UV spectrophotometry was used to analyze
`sulfadiazine (A = 309 mfi, 0.1 N HCI) and propylthiouracil (A =
`275 mp, HzO).
`
`RESULTS AND DISCUSSION
`Results, where possible, were plotted as percent of the amount
`ultimately dissolved so as to remove differences of overages occur-
`
`I
`
`/.-
`
`4
`
`12
`
`36
`28
`20
`MINUTES
`Figure 8-Dissolution
`rates of sulfadiazine capsule and tablets in
`simuIated gastric fluid T.S. Key: @, soft elastic capsule; 0, Tablet
`A ; and (3$ Tablet B.
`
`44
`
`52
`
`60
`
`1 Cat. No. XX30 025 00, Millipore Corp., Bedford, MA 01730
`
`4
`
`I
`8
`
`I
`I
`12
`16
`MINUTES
`Figure 5-Dissolution
`rates of reserpine capsule and tablets in
`simulated gastric fluid T.S. Key: 8, soft elastic capsule; 0, Tablet
`A; and (3, Tablet B.
`
`I
`20
`
`I
`24
`
`,
`28
`
`EXPERIMENTAL
`
`A drug must be formulated in one of several dosage forms, de-
`pending on its intended use. In general, a dosage form is designed
`for rapid and complete absorption of the drug. In some cases a
`dosage form may be developed for delayed action or for combined
`effects of quick onset and prolonged action. For rapid and complete
`absorption of a drug, it is best to formulate in solution. However,
`this is not always practical, as with very insoluble drugs. In this case
`the next best form is the suspension dosage form. Modern phar-
`maceutical technology embraces the use of surfactants and/or solubi-
`lizers to enhance the rapidity and maximum absorption of a drug.
`By nature, many surfactants and solubilizers are liquids at room
`temperature. Hence, these agents may play multifaceted roles in
`liquid formulations: as vehicles and interface modifiers. Formula-
`tions of a drug containing surfactants and/or solubilizers may be
`encapsulated conveniently in soft elastic capsules, as demonstrated
`in the present work which includes examples of relatively insoluble
`drugs.
`
`2o t’l
`h’ I
`
`36
`28
`20
`MINUTES
`Figure 6-Dissolution rates of digitoxin capsule and tablets in simu-
`lated gastric fluid T.S. Key: @, soft elastic capsule; 0, Tablet A ;
`and (3, Tablet B.
`
`I
`52
`
`I
`60
`
`4
`
`12
`
`44
`
`828 0 Journal of Pharmaceutical Sciences
`
`
`
`
`
`Table I-Dissolution Time in Minutes for 90% Drug Dissolved in Simulated Gastric Fluid at 37.5°
`
`
`
`
`
`Dose,
`Soft Elastic
`mg./
`Tablet A, Tablet B,
`
`Capsule Capsule,
`min.
`or Tablet min.
`min.
`Drug
`Hydrocortisone 5.0
`4.0 ± 0.2
`12 ± 1
`
`Ethinyl estradiol 0.05 4.2±0.1 60 ± 2
`Diethylstilbestrol
`4.2±0.1 96 ± 8
`0.5
`9 ± 0.5
`Phenobarbital 32.0
`3.1±0.3
`14 ± 2
`Reserpine
`0.25 3.9 ± 0.3
`Digitoxin
`70 ± 8
`4.2 ± 0.2
`0.2
`
`a Solution of drug encapsulated.
`
`4
`
`83 ± 2
`96 ± 8
`35 ± 2
`136 ± 8
`
`
`
`
`Table II-Amount in Micrograms of Drug Dissolved per Milliliter of Simulated Gastric
`
`
`Fluid at 37.5° after 5 Min. of Dissolution
`
`
`
`
`Dose,
`Soft Elastic
`mg./
`Tablet B,
`
`Capsule Capsule,a Tablet A,
`or Tablet mcg.frnl. mcg./ml. mcg./ml.
`Drug
`Bishydroxycoumarin
`0.6 ± 0.1
`25.0 5.9 ± 0.3
`715 ± 5
`Sulfadiazine 500.0 810 ± 5
`1.5 ± 0.5
`Phenylbutazone 100.0 100 ± 30
`
`Propylthiouracil
`50.0 980 ± 20
`380 ± 20
`
`•Suspension of drug encapsulated.
`
`310 ± 25
`250 ± 20
`
`parent solubility of the drug ranging from 1.1 to 67 times that of
`
`
`
`ring in different products. With practically insoluble drugs, where
`
`
`
`
`
`
`
`
`tablets reflecting the effects of the vehicle, solubiiizer, and surfactant.
`
`
`only a fraction of the dose is dissolved, the amount of drug dissolved
`
`
`The data indicate that it is possible to solubilize many low-dose,
`
`
`
`in 1 ml. of fluid was plotted dissolution time. Completion of
`versus
`
`
`
`relatively insoluble drugs and to encapsulate them in soft elastic
`
`
`
`dissolution, the saturation point in the case of poorly soluble drugs,
`
`
`
`capsules of appropriate sizes. For high-dose and very insoluble
`was taken as the time on the graph when a smooth curve through
`
`
`it is preferable to encapsulate them as suspensions. With the
`
`
`
`
`the points reached a maximum. Typical curves are shown in Figs.
`drugs,
`
`
`
`applications of these two techniques in encapsulation, conceivably
`
`I -10. Figures 1-6 are plots of percent drug dissolved time
`versus
`
`
`
`
`one can either singly or collectively use solubilizers and/or surfac
`
`
`
`from tablets and from solutions encapsulated in soft elastic capsules.
`
`
`
`tants as specially designed vehicles for each drug. The soft elastic
`dis
`
`Figures 7-10 are plots of milligrams or micrograms
`of drug
`
`capsule is an ideal dosage form for drugs such as the oral contra
`
`
`
`
`and for commercial tablets solved per milliliter of fluid versus time
`
`
`ceptives where submilligram unit doses are common.
`
`
`
`for suspensions encapsulated in soft elastic capsules. A cursory ob
`
`
`An appreciation of the profound influence dosage form design
`
`
`
`of that dissolution servation of Figs. 1-10 is sufficient to conclude
`
`
`has on dissolution, absorption, and efficacy (1-12) should preclude
`
`
`the drug from soft elastic capsules is faster than from tablets in
`
`
`
`sole reliance on conventional tablet and powder-filled capsule
`
`
`
`
`
`simulated gastric fluid T.S. (without pepsin) at 37.5°. However, a
`
`technology in the development of "new drug" dosage forms. The
`
`
`
`quantitative comparison may be made by observing the average
`
`
`time from duplicate runs for dissolution of 90% of the drug, as
`
`
`
`costs of carrying new drug dosage forms through toxicity studies,
`
`in clinical trials, and a new drug application procedure make errors
`
`
`
`
`
`
`shown in Table I. Table II lists the average amount in micrograms
`
`
`
`
`this area disastrous. Solutions and suspensions in soft elastic cap
`
`
`
`
`per insoluble drugs dissolved from duplicate runs of relatively
`
`
`
`sules, as well as tablets and dry-filled capsules, should be investigated
`
`
`
`
`milliliter offluid after 5 min. of dissolution. An examination of Table
`
`
`
`
`in early stages of development employing dissolution studies.
`
`I reveals that a drug, when formulated in soft elastic capsules, will
`in vitro
`
`
`by the more promising dosage forms should
`
`Availability as provided
`
`
`have a dissolution rate from 3 to 30 times faster than tablets. It is
`
`
`studies. then be appraised by in vivo animal
`
`
`
`apparent that the increase in dissolution rate is due to the rapid dis
`
`
`
`persion of the drug when the capsule splits open. Also, the use of a
`
`
`
`
`
`proper vehicle, solubilizer, and surfactant apparently helps to en
`CONCLUSIONS
`
`
`
`hance the dispersion of a relatively insoluble drug. Table II details
`
`
`
`The study illustrates the influence of oral dosage form design on
`
`
`
`
`the average increase, provided by the soft elastic capsule, in the ap-
`
`
`
`
`dissolution rates for drugs from different chemical and pharma-
`
`•
`
`-.
`
`.
`.
`
`• 1.0
`
`�0.8
`
`....: 300
`
`E ......�
`
` 200
`E
`d 100
`::,
`
`c::
`
`d ::,
`
` 0.6
`C:
`
`C C 0.4LJJ
`�
`0 � 0.2
`
`c
`
`4 12 20 28 36 44 52 60
`
`MINUTES
`
`1:11
`
`0
`
`20 24 28
`
`4 8 12 16
`MINUTES
`
`Figure 10---Dissolution rates of propylthiouracil
`Figure 9-Dissolu
`
`
`capsule and tablets
`
`
`tion rates of phenylbutazone capsule and tablet
`
`in simulated gastric fluid T.S. Key: e, soft elastic capsule; 0, Tablet
`
`fluid T.S. Key: e, soft elastic capsule; and 0, in simulated gastric
`
`
`A; and(), Tablet B.
`Tablet A.
`
`Vol. 59, No. 6, June 1970 0 829
`
`
`
`cological classes. It also suggests avenues that should not be over-
`looked when investigating new drugs or improving older medica-
`tions. The results demonstrate that many relatively insoluble drugs
`may be readily formulated in soft elastic capsules and have faster
`dissolution rates than tablets in that solutions or suspensions of a
`drug can be readily encapsulated. Furthermore, surfactants or other
`compounds may be encapsulated along with the drug so as to en-
`hance its solubility and potential absorption rate. Soft elastic cap-
`sules are recommended in the formulations of low-dose medication,
`of relatively insoluble drugs, and of drugs where early high-blood
`level of the drug is indicated.
`
`REFERENCES
`(1) E. Nelson, Clin. Pharmacol. Ther., 3, 673(1962).
`(2) P. J. Tannenbaum, E. Rosen, T. Flanagan, and A. P. Crosley,
`Jr., ibid., 9, 598(1968).
`(3) J. Wagner, E. S. Gerard, and D. G. Kaiser, ibid., 7 , 610
`(1966).
`(4) A. J. Aguiar, L. M. Wheeler, S. Fusari, and J. E. Zelmer,
`J. Pharm. Sci., 57, 1844(1968).
`(5) A. J. Glazko, A. W. Kinkel, W. C. Alegnani, and E. L.
`Holmes, Clin. Pharmacof. Ther., 9,4731968).
`(6) G. W. Brice and H. F. Hammer, J. Amer. Med. Ass., 208,
`1189( 1969).
`(7) S. Symchowicz and B. Katchen, J. Pharm. Sci., 57, 1383
`(1968).
`
`(8) W. E. Moore, G. A. Portmann, H. Stander, and E. W. M C
`Chesney, ibid., 54, 36(1965).
`(9) B. Calesnick, B. Katchen, and J. Black, ibid., 54,1277(1965).
`(10) F. A. Carnpagna, G. Cureton, R. A. Mirigian, and E.
`Nelson, ibid., 52, 605(1963).
`(1 1) G. Levy, N. A. Hall, and E. Nelson, Amer. J. Hosp. Pharm.,
`21,402(1964).
`(12) G. Levy, Can. Med. Ass. J., 90,978(1964).
`(13) J. C. Souder and W. C. Ellenbogen, Drug Stud., 26, 77
`(1958).
`(14) E. 0. Kreuger and E. B. Vliet, J. Pharm. Sci., 51, 181(1962).
`(15) “National Formulary,” 12th ed., Mack Publishing CO.,
`Easton, Pa., 1965; second suppl., 1967, p. 15.
`(16) “United States Pharmacopeia,” 17th rev., Mack Publishing
`Co., Easton, Pa., 1965.
`(17) L. Chafetz, M. Boudjouk, D. Tsilifonis, and F. S. Hom, J.
`Pharm. Sci., 57, lOOO(1968).
`(18) J. J. Burns, R. K. Rose, T. Chenkin, A. Goldman, A. Schu-
`lert, and B. B. Brodie, J. Pharmacol. Exp. Ther., 109,346(1953).
`
`ACKNOWLEDGMENTS AND ADDRESSES
`
`Received September 22, 1969, from the Research and Develop-
`ment Department, R. P. Scherer Corp., Detroit, MI 48213
`Accepted for publication December 11, 1969.
`
`DRUG STANDARDS
`
`Chemical Standardization and Quality Assurance of
`Whole Crude Coal Tar USP Utilizing GLC Procedures
`
`M. GRUBER, R. KLEIN, and M. FOXX
`
`Abstract [7 A procedure has been developed which utilizes gas-
`liquid chromatographic (GLC) analysis for the chemical standard-
`ization of medicinal crude coal tar USP. A similar method is
`recommended for the determination of coal tar fractions in Liquor
`Carbonis Detergens (LCD) (coal tar solution USP). Data con-
`firming that LCD and similar “extracts,” “fractionates,” and
`“synthetics” cannot be considered as generic, pharmaceutical, or
`medicinal equivalents of a properly standardized whole crude coal
`tar are presented.
`Keyphrases 0 Crude coal tar-analysis 0 Coal tar solution-
`Ethanol content, coal tar solution-determination 0
`analysis
`GLC-anal ysis.
`
`Dioscorides, a Greek physician, described nearly 2000
`years ago the merits of asphaltic tar in the “Materia
`Medica” as a treatment for cutaneous disorders (1). The
`advantages of the empirical use of “tars” were sub-
`sequently emphasized by numerous investigators in-
`cluding Brocq (2), White (3), and Goeckerman (4,5).
`In modern times, this medication is widely prescribed
`for various skin diseases, such as psoriasis and eczema,
`which are frequently severe and occasionally disabling.
`
`830
`
`Journal of Pharmaceutical Sciences
`
`In addition, this modality is routinely prescribed for
`seborrheic dermatitis, occupational and contact derma-
`titis, dermatophytosis, varicose eczema, chronic and
`exudative and lichenoid dermatitis, pruritis ani, and
`various other chronic skin disorders.
`Although therapeutic response is often dramatic, the
`known variability of coal tar composition and con-
`sequent inconsistency of clinical results has made this
`medication the subject of complaint and controversy
`among dermatologists.
`This ancient but fundamental topical drug is virtually
`devoid of any guardian standards of chemical composi-
`tion. Consequently, almost any coal tar, regardless of
`its composition, may satisfy the requirements of current
`official compendia for crude coal tar. Practically no
`controls have been established to assure uniformity,
`potency, safety, and efficacy. It is, therefore, quite
`evident that the scientific development of far more
`definitive drug reference standards and methods of
`analysis for this valuable, but variable, therapeutic agent
`is mandatory. No proficient effort has been initiated to
`create an effective method to control the physical and
`
`