WATER(cid:173)
`INSOLUBLE
`DRUG
`FORMULATION
`
`•
`
`\
`
`I
`
`Rong Liu
`Editor
`
`0001
`
`PSG2021
`Catalent Pharma Solutions v. Patheon Softgels
`IPR2018-00422
`
`

`

`Invitation to Authors
`
`lnterphann Press publishes books focused upon applied technology and regulatory
`affairs Impacting healthcare manufacturers worldwide. If you are considering
`writing or contributing to a book applicable to the phannaceutical, biotechnology,
`mec:fiCal device, diagnostic, cosmetic, or veterinary medicine manufacturing Industries,
`please contact our director of pubflcations.
`
`Library of Congress Cataloging-In-Publication Data
`Water-insoluble drug formation I Rong Uu, editor.
`p.cm.
`Includes bibliographical references.
`l. Solutions (Pharmacy) 2. Drugs--Solubility. I. llu, Jung.
`
`RS20 l.S6 W38 2000
`615'.42-<ic21
`
`10 9 8 7 6 54 3 2 1
`
`00-033450
`
`ISBN: 1-57491-105-8
`Copyright © 2000 by Interpharm Press. All rights reserved.
`
`All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored
`in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, pho(cid:173)
`tocopying, recording, or otherwise, without written permission from the publisher. Printed in
`the United States of America.
`Where a product trademark, registration mark, or other protected mark is made in the text,
`ownership of the mark remains with the Lawful owner of the mark. No claim, intentional or oth(cid:173)
`erwise, is made by reference to any such marks in this book.
`While every effon has been made by Interpharm Press to ensure the accuracy of the informa(cid:173)
`tion contained ln this book, this organization accepts no responsibility for errors or omissions.
`
`Interpharm Press
`15 Inverness Way E
`Englewood, CO 80112-Sn6
`
`Phone:+l-303-662- 9101
`Fax: + l-303-754-3953
`Orders/on-line catalog: www.interpharm.com
`
`0002
`
`

`

`17
`
`Soft Gelatin Capsules
`Developtnent
`
`S. Esmail Tabibi
`Shanker L. Gupta
`Pharmaceutical Resources Branch
`National Cancer Institute, NIH
`Bethesda, Maryland
`
`A pharmaceutical scientist will eventually face the task of formulating an oily or an oil(cid:173)
`soluble medicament in liquid formulation as a solid dosage form using the soft gela(cid:173)
`tin capsule, sometimes referred to as softgel or liquigel'™. In the formulation of com(cid:173)
`mon oral dosage forms, the formulator has access to excipients and processing
`technologies, thus enabling him to conduct a systematic formulation and process(cid:173)
`development research and produce an elegant and stable dosage form. On the other
`hand, due to its nature, the softgel technology has become specialized processing in
`which the formulator will rely on the others to produce the shell formulation and con(cid:173)
`ducts the shell-content compatibility studies. A suitable formulated medicament is
`finally encapsulated as the content into a compatible soft gelatin shell.
`Because of the highly cost-intensive operation of softgel capsule production, it is
`not possible for formulation scientists to conduct research on all phases of the for(cid:173)
`mulation and process development of soft gelatin capsules. However, based on the
`unique advantages and special properties of this type of dosage form, the formulators
`should familiarize themselves with the overall technology and processes involved
`both in the composition development and manufacturing aspects.
`Softgel capsules have gained popularity and use in the pharmaceutical industry
`for human and veterinary applications as an oral dosage form; as suppositories for
`
`609
`
`0003
`
`

`

`610 Water-Insoluble Drug Formulation
`
`rectal and vaginal administration; single-use applicators for ophthalmic, otic, and
`topical formulations; and rectal ointments. Their use in cosmetic industry is beyond
`the scope of this manuscript.
`Softgel capsules come in a variety of shapes, sizes, and colors that may be spe(cid:173)
`cific to the manufacturer. In Figure 17 .1, some representative shapes and sizes are pre(cid:173)
`sented. This chapter, provides an overview of the manufacturing methods, formula(cid:173)
`tion of the content medicament, the composition of the sheU, quality control
`procedures, stability, and shelf-life testing. We also discuss in some detail examples of
`the products formulated in softgel dosage form.
`
`MANUFACTURING METHODS
`
`Processing Equipment
`
`An exhaustive discussion on the advantages and disadvantages of different types of
`machinery used in the production of soft gelatin capsules is beyond the scope of this
`chapter. An excellent review by Stanley (1986) described the manufacturing process
`and formulation aspects of the softgel technology. A brief description of the various
`processing technologies follows.
`
`Plate Process
`
`Historically, the soft gelatin capsules were manufactured by the plate method, in
`which elasticized sheets of the formulated gelatin shell were placed on the die plate
`that contained a number of capsule-shaped cavities. By applying a vacuum, the gela(cid:173)
`tin was drawn into the cavities to form capsule wells. The capsule wells were then
`filled with drug formulation and covered by another sheet of the elasticized gelatin or
`the gelatin sheet was folded back over the filled wells. The upper plate was then placed
`on the top of the upper sheet and was pressed to form and cut the capsules. These
`capsules, generally, had one flat side. The major problems with this type of processing
`were the lack of dosage uniformity, high manufacturing losses, and that it was
`labor/cost intensive. This equipment is no longer available.
`
`Rotary Die Process
`
`According to Ebert ( 1977), Robert P. Scherer, in 1933, invented and perfected the rotary
`die process that almost eliminated all of the problems associated with the plate
`process and produced softgel dosage forms with improved uniformity and high stan(cid:173)
`dards of accuracy. This is the first continuous process in which the outer faces of two
`counterrotating rollers contain precisely machined and aligned die cavities. The die
`rollers rotate in opposite directions, and the matching die cavities from each die roller
`create the capsule pocket. Figure 17.2 presents a schematic view of the rotary die
`
`0004
`
`

`

`Figure 17.1 The shapes and sizes of commonly used soft-gelatin capsules.
`
`Nomination
`
`Rounds
`
`Shape 0
`
`Ovals
`
`Oblongs
`
`C) c
`
`Tubes
`
`Suppositories
`
`) ~ ~
`
`Optimum
`Optimum
`Optimum
`Optimum
`Optimum
`Capsule Fill Volume Capsule Fill Volume Capsule FlU Volume Capsule Fill Volume Capsule FlU Volume
`(minim)
`(minim)
`(minim)
`Size
`Size
`Size
`Size
`Size
`(minim)*
`(rninlm)
`
`3
`4
`5
`6
`7
`9
`15
`20
`40
`50
`80
`90
`
`3.0
`4.0
`5.0
`6.0
`7.0
`9.0
`15.0
`20.0
`40.0
`50.0
`65.0
`80.0
`
`2
`3
`4
`5
`6
`7'/ ~
`10
`12
`16
`20
`30
`40
`60
`80
`85
`
`2.3
`3.0
`4.0
`5.0
`6.0
`7.5
`10.0
`12.0
`16.0
`20.0
`30.0
`40.0
`60.0
`80.0
`85.0
`
`*A minim is equal ro 0.0616 mL
`
`3
`4
`5
`6
`8
`9'/ ~
`11
`12
`14
`16
`20
`
`3.0
`4.0
`5.0
`6.0
`8.0
`9.5
`11.0
`12.0
`14.0
`16.0
`20.0
`
`:i
`4
`5
`6
`8
`17 1
`/ l
`30
`45
`65
`90
`120
`
`3.0
`4.0
`5.0
`6.0
`8.0
`17.5
`32.0
`45.0
`65.0
`90.0
`120.0
`
`10
`17
`40
`80
`
`10.0
`17.0
`40.0
`80.0
`
`(7) --
`
`0005
`
`

`

`612 Water-Insoluble Drug Formulation
`
`Figure 17.2 The rotary die encapsulating machine. [Source: Courtesy of Banner
`Pharmacaps, Inc.]
`
`Fill Material Leads
`
`Counter
`Rotating
`Capsule
`Dies
`
`Gelatin
`Netting
`
`process. The process is automatic and produces capsules in various shapes and sizes.
`In this process, the elasticized shell formulation converts into two ribbons, and the
`formulation of the medicament, either in the liquid or in the paste form, is simulta(cid:173)
`neously pumped between the rotating rollers. The injection pressure of the formu(cid:173)
`lated content of the capsule causes the gelatin ribbons to swell into the die cavity,
`which becomes filled with the formulation. The convergence between the synchro(cid:173)
`nized counterrotating rollers hermetically seals and severs the completed capsules
`from the ribbons. The precise and extremely low clearance of the rotating parts
`demands continuous lubrication of the machine to avoid even a slight buildup. The
`lubrication oil should, therefore, be a generally recognized as safe (GRAS) material. The
`formed capsules, immediately after manufacture, automatically undergo volatile sol(cid:173)
`vent washing to remove any traces of lubricating oil from the exterior of the capsules.
`The capsule is then conveyed to a drying station and dried on uays, either in air or
`under vacuum, to an equilibrium moisture content with forced conditioned air of
`20 percent to 30 percent relative humidity at 21 o C to 24° C (Stanley 1986). The drying
`technique may proceed with an infrared drying step to speed up the process. At this
`point, lhe shell contains 6 percent to 10 percent moisture based on the gelatin formu(cid:173)
`lation used to produce the shell. The dried capsules is then transferred to the inspec(cid:173)
`tion station and sampled for release. After performing the required quality control
`tests for size and color sorting, final counting, packaging, and labeling is done. Brand-
`
`0006
`
`

`

`Soft Gelatin Capsules Development 613
`
`Figure 17.3 The total production process. From preparation of shell and fill material
`composition to counting and packaging finished product, the state-of-the-art equip(cid:173)
`ment used for each step of the process. [Source: Courtesy of Banner Pharmacaps, Inc.)
`
`Fill
`Material
`
`~
`
`' J
`
`Gelatin
`
`Encapsulation
`
`Washing
`
`Tumble Drying
`
`Spreading
`
`Tunnel Drying
`
`Inspection
`
`Size Sorting
`
`Counting and
`Packaging
`
`Shipping
`
`ing, if desired, may be done by either heat branding or ink printing at the finishing
`department. All of these steps may be integrated into a continuous operation by
`employing proper equipment at each step. Figure 17.3 depicts the schematic presen(cid:173)
`tation of the entire process.
`Following the success of rotary die process, the Norton Company in 1949
`announced the development of another continuous soft gelatin capsule processing
`technology known as reciprocating die process.
`
`0007
`
`

`

`614 Water-Insoluble Drug Formulation
`
`Figure 17.4 Schematic presentation of Globex Mark II capsule-filling machine.
`[Source: Courtesy of Kinematic & Control Corp.]
`
`Filler
`;==~I Gelatin
`~ Coolant Oil
`l.
`
`Automatic
`Valve
`
`Gelatin
`
`Capsule
`Receiver
`
`' - - - - -
`
`-
`
`Coolant
`Filter and
`Pump
`
`I' I
`
`•
`.
`S1eve • /
`•
`.,/
`
`---1
`
`r;-~
`,(~
`
`~
`
`I
`1
`
`1
`
`I
`
`Filler
`
`Filter
`
`Pulsator
`Pump
`
`Capsule formation
`by means of
`artificial constriction
`of concentric tube of
`hiler surrounded by
`molten gelatin
`
`Cooling Column
`
`•
`
`.
`c.? I
`,,
`,,
`l
`I!
`j
`
`L- . --J)
`
`I
`I
`_ _j
`
`Accogel Process
`
`Although rotary die process and reciprocating die process were both capable of pro(cid:173)
`ducing soft gelatin capsules containing oily liquids and pastes, the incorporation of
`powders into soft gelatin capsules was made possible by Accogel process (Augsburger
`1996). A rotary process, also developed in 1949 by Lederle Laboratories, is a continu(cid:173)
`ous process that produces softgel capsules comaining granules and powders. Briefly.
`the process involves a measuring roll that holds the fill formulation in its cavities
`under the vacuum and rotates directly above the elasticized sheet of the gelatin rib(cid:173)
`bon. The ribbon was drawn into the capsule cavities of the capsule die rolL by vacuum.
`
`0008
`
`

`

`Soft Gelatin Capsules Development 615
`
`The measuring rolls empty the fill material into the capsule-shaped gelatin cavities on
`the die roll. The die roU then converges with the rotating sealing roll covered with
`another sheet of elasticized gelatin. The convergence of two rotary rolls creates pres(cid:173)
`sure to seal and cut the formed capsules.
`
`Seamless Process
`
`Truly seamless one-piece, soft gelatin capsules were produced by the G/obex Mark 11
`Capsulator, which does not require dies. Figure 17.4 schematically shows this process.
`In this process, a molten-gelatin stream nows through the outer nozzle of a concen(cid:173)
`tric tube at a constant rate, and a precision metering pump dispenses the medicated
`liquid formulation through the inner orifice. This method is often referred to as a bub(cid:173)
`ble method that creates seamless, spherical softgel capsules called pearL The process
`uses the pulsating mechanism at the orifice to force the emerging stream to break up
`into an intermittent but steady flow of uniformly sized, tubular-shaped composite
`droplets into an immiscible cooling oil. The fundamental principles of interface
`physics-the tendency of liquids to form spherical drops due to surface tension(cid:173)
`transforms tubular-shaped drops into a spherical shape. The congealed gelatin on
`cooling envelops the core medicated formulation with an even shell. The cooling oil
`quickly carries the formed capsule away from the pulsating nozzle, slowly congeals
`the gelatin, and automatically ejects the capsules from the system as a one-piece, soft
`gelatin capsule (Augsburger 1996; Rakucewicz 1986). Unlike the previous methods,
`the drying in this process involves a cooling step to allow the gelatin shell to congeal
`(Rakucewicz). The separated capsules from the oil must be thoroughly washed and
`degreased by a volatile solvent and spread for drying in a suitable dryer (Augsburger;
`Rakucewicz).
`
`FORMULATION CONSIDERATIONS
`
`An important consideration in the development of soft gelatin capsules is the com(cid:173)
`position of the fill content, be it solution, suspension, or solid. The contents of soft gel(cid:173)
`atin capsules vary from solids, solid in liquid, solution or suspension, a combination
`of miscible liquid, or a simple liquid formulation. It is critical that each formulation is
`carefully developed depending on the physicochemical characteristics of the drug
`molecule. An optimum formulation consists of a minimum volume or weight that can
`be filled in the smallest possible capsule for ease of administration and for maximum
`therapeutic effectiveness. In Table 17.1, composition of the capsule content and in
`Table 17.2, shell composition of commonly available commercial products are presented.
`Stella et al. (1978) reported formulation of a hydrophobic amine, an antimalarial
`compound, into soft gelatin capsule using oleic acid as a solvent. Initially, the solubil(cid:173)
`ity of the drug was determined in oleic acid. It was found that the drug was soluble in
`oleic acid in concentrations up to 23 percent w/w. The soft gelatin formulation in oleic
`acid improved bioavailability of this antimalarial drug significantly over the standard
`
`0009
`
`

`

`Table 17.1
`The Content Composition of Commercially Available Products
`
`Product
`
`Generic Name
`
`Oils
`
`AquasolA
`
`Depakene
`VePesid
`
`Lanox:icaps
`
`Zanrac
`
`Retinol (Vitamin A)
`
`Valproic Acid
`Etoposide (VP-16)
`
`Digoxin
`
`Ranitidine HCI
`
`Corn Oil
`
`Coconut Oil and
`Triglycerides
`
`Content Composition•
`
`Water-MJsclble
`Solvents
`
`Other
`Ingredients
`
`Surface-Active
`Agents
`
`Polysorbate 80
`
`Glycerin, PEG-400
`
`Citric Acid, Water
`
`PG, PEG-400, Ethanol
`
`Oxsoralen-Uitra
`
`Methoxsalen
`
`Content composition is not available
`
`IOmg
`
`20mg
`
`Adalat
`
`:--Jorvir
`
`Nifedipine
`
`Peppermint
`
`PEG 400, Glycerin
`
`Na Saccharine
`
`Ritonavir
`
`Caprilic/Capric
`Triglycerides
`
`PG, Ethanol
`
`Citric Acid
`
`Polyglycolyzed
`Glycerides,
`Polysorbate 80
`
`Nimowp
`
`Nimodipine
`
`Peppermint Oil
`
`Glycerin, PEG 400
`
`Water
`
`Unisom SleepGel
`
`Diphenhydramine HQ
`
`PG, PEG•
`
`Nifedipine
`
`Peppermint Oil
`
`PEG 400, Glycerin
`
`Procardia
`
`lOmg
`
`20mg
`
`10 mg
`
`Accutane
`
`20mg
`
`lsotretinoin
`
`40mg
`
`Soybean Oil,
`Beeswax,
`Hydrogenated
`Soybean and
`Vegetable Oils
`
`Na Saccharine
`
`Na Edetate
`andBHA
`
`Continued on next page.
`
`0010
`
`

`

`Table 171, conrinuedfrom previous page.
`
`Marino!
`
`2.5mg
`Smg Dronabinol
`(B-9-THC)
`lOmg
`
`25 rng
`
`Sandimrnune 50mg Cyclosporine
`lOOmg
`
`Chromogen
`
`Dox:idan Uqui-Gels
`
`Surfak
`
`Atromid-S
`
`Gin sana
`
`Ferrous Sulfate,
`Ascorbic Acid,
`Cyanocobalamin,
`and Desiccated
`Stomach Substance
`
`Casanthranol and
`Docusate Sodium
`
`Docusate Calcium
`
`Clofibrate
`Standardized Ginseng
`Extract
`
`Vesanoid
`
`'Iretinoin
`
`Sesame Oil
`
`ComOU'
`Labrafil M 2125 CS
`
`Ethanol
`
`Content composition is not available.
`
`PEG•
`
`Com Oil
`
`Sunflower Oil,
`Beeswax
`
`Beeswax,
`Hyrogenated
`Vegetable Oils,
`Hydrogenated
`Soybean Oil
`Flakes, and
`Soybean Oil
`
`Correctol Stool Softner Docusate sodium
`
`PEG-400, PG
`
`Neoral
`
`25 rng
`
`100 mg
`
`Cyclosporine
`
`Corn Oil
`
`PG, Ethanol
`
`Lecithin,
`Chlorophyll
`
`Disodium Edetate,
`BHA
`
`DL-(AJpha)
`Tocopherol
`
`Polyoxyl40
`Hydrogenated
`Castor Oil
`
`Continued on ne:cr page.
`
`0011
`
`

`

`Table 17.1, conrinued from previous page.
`
`Product
`
`Generic Name
`
`Olls
`
`Content Composition•
`
`VVater-~sclble
`Solvents
`
`Other
`Ingredients
`
`Surface-Active
`Agents
`
`PhosChol 900
`Nytol
`
`Protegra
`
`Phosphatidyl-choline
`Diphenhydramine HCl
`
`An tiox:idan t Vitamins
`& Mineral Supplement
`
`Alka-Sel!zer Plus
`
`One-A-Day
`Antioxidant Plus
`
`Various Analgesics
`and Decongestants
`Antioxidant Vitamins
`& Mineral Supplement
`
`One-A-Day Garlic
`Vicks DayQuil
`
`Vicks NyQuil
`
`Garlic Oil Macerate
`Various Analgesics and
`Decongestants
`Various Analgesics and
`Decongestants Plus
`Doxylamine Succinate
`
`Phayzyme- 125
`
`Simethicone
`
`Content composition is not available.
`PEG*
`
`Cottonseed Oil,
`Soybean Oil,
`Beeswax
`
`PEG•
`
`Soybean Oil,
`Beeswax, Panially
`Hydrogenated
`Vegetable Oils
`
`Calcium Phosphate
`
`Potassium Acetate,
`Povidone, Water
`
`Lecithin
`
`PG, PEG•
`
`Xylose
`Povidone, Water
`
`PG , PEG•
`
`Povidone, Water
`
`Soybean Oil,
`Yellow Wax,
`Hydrogen ated
`Soybean Oil,
`and Vegetable
`Shortening
`
`Lecithin and
`Polysorbate 80
`
`Robitussin Night-
`Time Cold
`
`Acetaminophen,
`Pseudoephedrine HCl,
`Dextromethorphan HBr,
`and Doxylamine Succinate
`
`PG,PEG•
`
`Povidone, Sodium
`Acetate, and
`Water
`
`Sorbitan•
`
`Continm•d on next page.
`
`0012
`
`

`

`Table I 7. I, conrirwed from previous page.
`
`Robitussin Severe
`
`Robitussin C&C
`UquiGels
`
`Robitussin C&C
`Flu
`
`Dimetapp
`Uqui-Gels
`
`Dimetapp C&C
`Uqui-Gels
`
`Chromogen Forte
`
`Chromogen f.A
`
`Gas-X
`
`Sleepinal
`UniqueE
`
`Super EPA
`
`Guaifenesin and
`Pseudoephedrine HCI
`
`Gu aifenesin,
`Pseudoephedrine HCl,
`Dextromethorphan HBr
`Acetaminophen,
`Guaifenesin Pseudo-
`ephedrine HCl, and
`Dextromethorphan HBr
`
`Brompheniramine
`Maleate and Phenylpro-
`panolamine, I lCI
`
`Brompheniramine
`Maleate, Phenylpro-
`panolamine HCl. and
`Dextromethorphan HBr
`Ferrous Fumarate, Ascorbic
`Acid, Folic Acid, and
`Cyanocobalamin
`
`Ferrous Fumarate, Ascorbic
`Acid, Folic Acid, and
`Cyanocobalamin
`
`Simethicone
`
`Diphenhydramine HCJ
`Mixed Tocopherols
`
`Omega-3
`
`Benadryl Day-f.ree
`Nutr-E-Sol
`
`Diphenhydramine HCl
`Vitamin E
`
`PG, PEG"
`
`PG,PEG•
`
`PG, PEG"
`
`PG, PEG"
`
`PG, PEG"
`
`Sorbitan•
`
`Povidone, Sodium
`Acetate, and Water
`Povidone, Sodium
`Acetate, and Water Sorbitan"
`
`Povidone, Sodium
`Acetate, and Water Sorbitan•
`
`Povidone. Sodium
`Acetate. and Water Sorbitan•
`
`Povidone, Sodium
`Acetate, and Water Sorbitan•
`
`Content composition is not available.
`
`Content composition is not available.
`
`PG, PEG-400
`
`Povidone, Water
`
`Continued on next page.
`
`0) -c.o
`
`0013
`
`

`

`0)
`N
`0
`
`Tnhle 17 I , continued from prrwious pngP.
`
`Product
`
`Generic Name
`
`Oils
`
`Content Composition•
`
`\Vater-~lsclble
`Solvents
`
`Other
`Ingredients
`
`Surface-Active
`Agents
`
`Breath Plus
`
`Alka-Seltzer
`Plus Flu
`
`Hytrin
`
`ALKYROL
`
`1 mg
`
`2mg
`
`S mg
`
`10 mg
`
`250 mg
`SOOmg
`
`Parsley Seed Oil,
`Peppermint Oil, Vitamin
`E, and Beta Carotene
`Acetaminophen,
`Pseudoephedrine HO,
`and Dextromethorphan
`HBr
`
`Sunflower Oil
`
`Chlorophyll
`
`PG
`
`Povidone, Potassium
`Acetate
`
`Terazosin Hydrochloride
`
`Mineral Oil
`
`PG
`
`Povidone
`
`Aalkylglycerols
`
`BHA = Buthylated Hydroxy Anisole, PG = Propylene Glycol, and PEG= Polyethylene Glycol.
`•JYpe is not provided.
`rrom Physicians Desk Reference (1998).
`
`0014
`
`

`

`Table 17.2
`The Shell Composition of Commercially Available Products
`
`Parabens
`
`Shell Composition
`
`Color
`
`Product
`
`Generic Name
`
`Methyl Propyl Gelatin Glycerin
`
`FD&C
`
`Others
`
`1102
`
`Other
`Ingredients
`
`Aquasoi A
`
`Depakene
`
`VcPesid
`Lanoxicaps
`
`Zantac
`
`Retinol (Vitamin A)
`
`VaJproic Acid
`
`Etoposide (VP-16)
`
`Digoxin
`
`Ranitidinc HCI
`
`X
`
`X
`
`X
`
`X
`
`X(?)
`
`X
`
`X
`
`X
`
`X
`X('?)
`
`Oxsoralcn-Ultta
`
`MethoxsaJen
`
`Ada! at
`
`Norvir
`
`Nimotop
`
`Nifedipine
`
`Ritonavir
`
`Nimodipine
`
`Unisom SleepGel
`
`Procardia
`
`Diphenhydramine
`HCl
`Nifedipine
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`lOmg
`
`Accurane
`
`20mg
`
`40mg
`
`Isotretinoin
`
`X
`
`X
`
`X
`
`X
`
`Yellow #6
`
`Iron Oxide
`
`Iron Oxide
`
`Red#3
`Blue Il l
`
`Yellow#6
`and #10
`
`Red #40
`
`Ethy Vanillin
`
`Yellow #6
`
`Iron Ox.id
`
`Iron Oxid
`
`X
`
`X
`
`Sorbitol
`
`Sorbitol
`
`X
`
`X
`
`X
`
`X
`
`Blue #I
`
`Yellow#6
`Blue #1
`Red #40
`
`Shell composition is not available.
`
`X
`
`Yellow #6
`
`Iron Oxide
`
`Shell composition is not available.
`
`X
`
`X
`
`Blue #1
`
`X
`
`Sorbitol
`
`I
`
`X
`
`X
`
`X
`
`X
`
`X
`
`Inert
`Ingredients
`
`Sorbitol
`
`Pharmaceutical
`Glaze
`
`Inert
`Ingredients
`
`en
`N ......
`
`Continued on next page.
`
`0015
`
`

`

`Table 17.2. corttinued frum preLtious page.
`
`Parabens
`
`Shell Composition
`
`Color
`
`Product
`
`Generic Name
`
`Methyl Propyl Gelatin Glycerin
`
`FD&C
`
`Others
`
`Ti02
`
`Marino!
`
`2.5mg
`
`Smg Dronabinol
`(S-9-THC)
`
`IOmg
`
`X
`
`X
`
`X
`
`X
`
`Yellow #6
`
`X
`
`Yellow #6
`
`Other
`Ingredients
`
`Cyclosporine
`
`X
`
`X
`
`Red Iron
`Oxide
`
`Yellow Iron
`Oxide
`
`X Sorbitol
`
`Shell composilion is not available.
`
`Blue Il l
`Red #40
`
`Blue 11 1
`Red #40
`
`Blue # l
`Red #26
`Red# 40
`Yellow 116
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X Sorbitol
`
`Sorbitol
`
`Other
`Ingredients
`
`D&C
`Red #28
`Red #30
`Yellow #10
`
`Red andYel-
`low Iron
`Oxide
`
`X
`
`Chlorophyll
`
`Continued on next page.
`
`Sand immune
`
`25 &
`100 mg
`
`50 mg
`
`Chromogen
`
`Dox.idan
`Liqui-Gels
`
`Surfak
`
`Ferrous Sulfate,
`Ascorbic Acid,
`Cyanocobalamin,
`and Desiccated
`Stomach Substance
`
`Casanthranol and
`Docusate Sodium
`
`Docusate Calcium
`
`X
`
`X
`
`Atromid-S
`
`Clofibrate
`
`Ginsana
`
`Standardized
`Ginseng Extract
`
`Vesanoid
`
`Tretinoin
`
`X
`
`X
`
`0016
`
`

`

`Table 17.2, continued from previous page.
`
`Correctol Stool
`Softner
`PhosChol 900
`
`Nytol
`
`Protegra
`
`Alka-Seltzer Plus
`
`One-A-Day
`Antioxidant Plus
`
`Docusate Sodium
`
`Phosphatidyl-choline
`
`Diphenhydramine
`HCJ
`Antioxidant
`Vitamins & Mineral
`Supplement
`
`Various Analgesics
`and Decongestants
`
`Antioxidant Vitamins
`& Mineral
`Supplement
`
`One-A-Day Garlic
`
`Garlic Oil Macerate
`
`Vicks DayQuil
`
`Vick.s NyQuil
`
`Various Analgezics
`and Decongestants
`
`Various Analgezics
`and Decongestants
`Plus Doxylamine
`Succinate
`
`Phay-.cyme-125
`
`Simethicone
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`Yellow#6 D&C
`Red #40
`Red #33
`Shell composition is not available.
`
`Sorbitol
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`Sorbitol
`
`Edible Ink
`
`Red #40
`Blue #1
`
`X
`
`Edible Ink (?)
`
`Yellow #5 Artificial
`Colors
`
`X Sorbitol
`
`Yellow #5
`
`Artificial
`Colors
`
`X
`
`Red f/40
`Yellow#6
`
`Yellow #10
`Blue #l
`
`Sorbitol
`
`Sorbitol
`
`Sorbitol (?)
`
`Red #40
`
`X
`
`Continued on next page.
`
`0017
`
`

`

`Table 17.2, continued from prevwus page.
`
`Product
`
`Generic Name
`
`Methyl Propyl Gelatin Glycerin
`
`FD&C
`
`Others
`
`TI02
`
`Parabens
`
`Shell Composition
`
`Color
`
`Robitussin
`Night-Time Cold
`
`Robirussin Severe
`
`Robitussin C&C
`LiquiGels
`
`Robitussin C&C
`Flu
`
`Dimetapp Uqui-
`Gels
`
`Dimetapp C&C
`Uqui-Gels
`
`....
`
`Acetaminophen,
`Pseudoephedrine
`HCI. Dextrometh-
`orphan HBr, and
`Doxylamine
`Succinate
`
`Guaifenesin and
`Pseudoephedrine
`HCl
`Gualfenesin,
`Pseudoephedrine
`HCl, Dextrometho-
`rphan HBr
`
`Acetaminophen,
`Guaifenesin, Pseudo-
`ephedrine HCI, and
`Dexlromelhorphan
`HBr
`Brompheniramine
`Maleate Phenylpro-
`panolamine HCl
`
`Brompheniramine
`Maleate, Phenylpro-
`panolarnine I ICI,
`and Dextrometho-
`rphan HBr
`
`Green #3
`D&C
`YeUow#6 Green #5
`and
`Yellow
`#10
`
`Green 113
`
`Blue #1
`Red #40
`
`Red #40
`Yellow #10
`
`Red #33
`
`Red #40
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`Other
`Ingredients
`
`Manni to,
`Sorbitol
`
`Pharmaceutical
`Glaze
`
`Manni to,
`
`Pharmaceutical
`
`Sorbitol
`
`Glaze
`
`X
`
`X
`
`X Mannito.
`Sorbitol
`
`Pharmaceutical
`Glaze
`
`Mannito,
`Sorbitol
`
`Manni to,
`Sorbitol
`
`Pharmaceutical
`Glaze
`
`Mannito,
`Sorbitol
`
`Pharmaceutical
`Glaze
`
`X
`
`X
`
`Continued on ne.xc page.
`
`0018
`
`

`

`Table 17.2, continued frum previous page.
`
`Chromogen
`Fone
`
`Chromogen FA
`
`Neoral
`
`Gas-X
`
`Ferrous Fumarate,
`Ascorbic Acid, Folic
`Acid, and
`Cyanocobalamin
`Ferrous Fumarate,
`Ascorbic Acid, Folic
`Acid, and
`Cyanocobalamin
`
`Cyclosporine
`
`Simethicone
`
`Correctol Stool
`Softner
`
`Sleepinal
`
`Docusate sodium
`
`Diphenhydramine HCl
`
`Shell composition is not available
`
`Shell composition is not available.
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`Iron Oxide
`
`X
`
`X
`
`Sorbitol
`
`Other
`Ingredients
`Peppermint
`Oil
`
`Blue #l
`Red #40
`Yellow# lO
`
`Yellow #6
`Red #40
`
`D&C
`Red #33
`
`Blue #1 (?) D&C
`Green #3 (?) Yellow #10
`
`Sorbitol
`
`Sorbitol
`
`Shell composition is not available.
`
`Shell composition is not available.
`
`Shell composition is not available.
`
`UniqueE
`Nutr-E-Sol
`
`SuperEPA
`
`Benadryl
`Day-Free
`
`Mixed Tocopherols
`
`Vitamin E
`
`Omega-3
`
`Diphenhydramine HO
`
`X
`
`X
`
`Sorbitol
`
`Contin ued 011 next page.
`
`0019
`
`

`

`Table 17.2. conrinued from previous page.
`
`Product
`
`Generic Name
`
`Methyl Propyl
`
`Gelatin Glycerin
`
`FD&C
`
`Others
`
`Para hens
`
`Shell Composition
`
`Color
`
`·noz
`
`Other
`Ingredients
`
`Breath Plus
`
`Alka-Seltzer Plus
`rlu
`
`1 mg
`
`2 mg
`
`Smg
`
`IOmg
`
`250mg
`
`SOOmg
`
`Hytrin
`
`All.'YROL
`
`Sunflower Oil, Parsley
`Seed Oil, Peppermint
`Oil, Chlorophyll,
`Vitamin E. and Beta
`Carotene
`Acetaminophen,
`Pseudoephedrine
`HCl. and Dextro-
`methorphan HBr
`
`Shell composition is not available
`
`X
`
`X
`
`Red #40
`
`X
`
`Sorbitol
`
`Terazosin
`Hydrochloride
`
`X
`
`X
`
`X
`
`X
`
`lron Oxide
`D&C
`Yellow #10
`
`D&C
`Red #28
`
`Red #40
`
`Blue #1
`
`X
`
`Vanillin
`
`AalkylglycerolsShell composition is not available
`
`(?) Denotes that the ingredient may exist in the shell composition.
`From Pllysici.ans Desk Reference (1998).
`
`0020
`
`

`

`Soft Gelatin Capsules Development 621
`
`hard-gelatin capsule formulation. The mean area under the curve (AUC) for hard(cid:173)
`gelatin capsule formulation was 16 percent (±10 percent) of the AUC for soft gelatin
`capsule formulation in this study conducted in beagle dogs by means of a crossover
`experimental design (Stella et al. 1978). At the National Cancer Institute, a majority of
`the molecules under development are hydrophobic in nature (Vishnuvajjala et al.
`1994). The solubility and stability of these molecules are detemtined prior to dosage
`form-considerations. For example, the solubility of NSC 338720 (Penclomedine) was
`determined in various vehicles suitable for soft gelatin capsule formulation, the data
`are presented in Table 17 .3.
`As can be seen, the liquids under consideration are water-immiscible liquids
`such as vegetable oils (corn oil, peanut oil), long-chain triglycerides (trioctanoin), and
`medium-chain triglycerides (Neobee M-5). The solubility of Penclomedine is 150 to
`200 mg/mL in these water-immiscible vehicles, which is convenient for dissolving a
`maximum amount of drug in a minimum amount of vehicle for a given capsule size. A
`small-scale pilot batch of the product was prepared in representative vehicles-com
`oil, trioctanoin, Neobee M -5 in the presence and absence of surfactant Tween 80-and
`placed on stability at accelerated temperatures. It is possible that there is migration of
`water from the capsule shell into the cavity during the manufacture of softgel capsules
`or shelf-life storage, thereby forming a cosolvent containing organic solvent and water
`resulting in precipilation of a water-insoluble drug in the capsule cavity. The surfactant
`is, therefore, sometimes added to aid in the dissolution of active drug in the cosolvent
`mixture. It also helps in the enhancement of oral bioavailability of the active drug by
`emulsifying the oil solution in the gastrointestinal tract (Kwong et al. 1994).
`
`Table 17.3
`Solubility of Penclomedine in Various Vehicles at 25° C
`
`Vehicle
`
`Solubility (mglmL)
`
`Water
`Acetate Buffer (pH 4)
`Carbonate Buffer (pH 9)
`0.1 N HCI
`0.1 N NaOH
`Tributyrin
`Neobee M-s·
`Olive Oil
`Soybean Oil
`Soybean Oil with 1 percent 1\veen
`Corn Oil
`Peanut Oil
`Sunflower Oil
`Safflower Oil
`Trioctanoin
`
`• A fractionated coconut oil.
`
`< 1
`<1
`< 1
`<I
`< 1
`289
`224
`163
`177
`172
`174
`165
`177
`186
`230
`
`0021
`
`

`

`628 Water-Insoluble Drug Formulation
`
`Another important consideration is the stability of the drug at 35° C to 40° C
`because of processing requirements of soft gelatin capsules; fill materials may be
`heated up to 35° C during encapsulation. The stability data for the pilot scale batch of
`Penclomedine is presented in Figure 17.5. The data indicate that this drug is fairly sta(cid:173)
`ble in various vehicles under consideration. A human Phase 1 clinical batch in Neobee
`Oil was produced, and its shelf-life surveillance at controlled room temperature has
`shown 3 years of stability.
`Similar developmental studies were conducted for another experimental anti(cid:173)
`liN compound, NSC 629243, a thiocarbamate (http:/ /dtp.nci.nih.gov). This molecule
`has very poor water solubility (<1 mg/rnL). Solubility studies were conducted to find
`a suitable solvent for soft gelatin encapsulation. Based on the solubility data, sesame
`oil (64 mg/mL) and MiglyoJ® (fractionated coconut oil, BP; 140 mg/mL) were chosen
`for further evaluation. In the case of sesame oil, antioxidants-BHA/BHT mixture and
`three different concentrations of thioglycolic acids, 0.1 percent, 0.5 percent, and 1.0
`percent (v/v)-were evaluated to determine their ability to protect against further
`degradation of the drug due to oxidation reaction (Strickley and Anderson 1993). Sim(cid:173)
`ilar studies were conducted in Miglyol formulations in the presence of a surfactant
`and an antioxidant. In these studies, Miglyol formulations did not show any degrada(cid:173)
`tion at elevated temperatures when compared with sesame oil formulations. Further
`studies were performed in actual soft gelatin capsules with two representative formu-
`
`Figure 17.5 Long-term stability of concentrated solutions (200 mg/mL) of Pen(cid:173)
`clomedine in Neobee M-5 with (filled symbols) and without 0.5 percent 1Ween 80 at
`various temperatures.
`
`• • o
`
`. b.
`
`0
`
`100
`
`99
`
`98
`
`97
`
`96
`
`0)
`.s
`c
`lij
`E
`Cl)
`0:
`0>
`::l
`
`Ci
`c
`Cl)
`~
`(f
`
`0 SO"C
`• sooc
`
`0 37° C
`• 37' C
`
`b. Ambient
`A Ambient
`
`. o
`B
`•
`•
`
`b.
`I~
`•
`
`95 4------------.------------r-----------.-----------~
`
`0
`
`50
`
`100
`
`150
`
`200
`
`Storage Time (Days)
`
`0022
`
`

`

`Soft Gelatin Capsules Development 629
`
`lations-Miglyol alone and sesame oil containing l.O percent (v/v) thioglycolic acid as
`an antioxidant. In an accelerated stability study conducted for 6 months using soft
`gelatin capsule formulations, Miglyol formulations demonstrated superior stability
`over sesame oil, presumably because it is a saturated oil, which affords improved sta(cid:173)
`bility against oxidation.
`It is also possible to dissolve hydrophobic drugs in water-miscible organic sol(cid:173)
`vents such as polyethylene glycol400 (used with CAl, NSC 609974; V1shnuvajjala et al.
`1994); Gelucire 44/ 14* (a proprietary solvent that is a mixture of glyceryl and polyeth(cid:173)
`ylene glycoll500 esters of fatty acids); cosolvent mixtures containing various propor(cid:173)
`tions of medium-chain triglycerides; polyoxyl 35 castor oil (Cremophor EU~); and
`polyglycolized glycerides (e.g., commercial formulation of anti-HIV protease inhibitor,
`ritonavir; PDR 1998). However, some of these excipients can cause migration of water
`from the soft gelatin capsule shell (water content range lO percent to 20 percent) into
`the capsule cavity, thereby causing precipitation of the active drug substance. Serajud(cid:173)
`din, Sheen, and Augustine (1986) reported that water migration from the shell resulted
`in crystallization of a water-insoluble drug under development.
`One of the solvents commonly used as a pharmaceutical aid for dissolution of
`hydrophobic drugs is ethanol. However, for drugs to be used in soft gelatin capsules,
`ethanol cannot be used easily because ethanol diffuses quite readily through soft gel(cid:173)
`atin fllms (Moreton and Armstrong 1995) at a fairly rapid rate. The diffusion is fast
`enough that most of the ethanol would diffuse out through the drying phase during
`the manufacture of softgel capsules. Moreton and Armstrong, in another study (1998),
`found that c