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FVolume 12 Number 1
January 2014 $15.00
PPo r m u l a t i o n r o d u c t i o n a c k a g i n g
TABLETS&CAPSULES
Formulating a liquid-filled capsuleImproving capsule filling
efficiency
The ABCs of roller compactionINTERPHEX preview
aA-DIGICover_Cover 1/8/14 10:46 AM Page C1
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A10 January 2014 Tablets & Capsules
formulationA rapid vehicle-screeningapproach for formulatinga
low-solubility compoundinto liquid-filled capsules
Amol Kheur, Anil Kane, MohammadAleem, and Maureen
McLaughlinPatheon Pharmaceutical Development Services
Kiran Kumar Tumbalam and Shivaprakash PoojaryFormerly of
Patheon
For a drug product to exert its therapeutic effect, it must be
sol-uble in an aqueous environment. This ensures that the
activepharmaceutical ingredient (API) will provide sufficient
concen-tration to induce gastrointestinal (GI) tract absorption.
Hence,molecules with promising pharmacodynamics yet poor
solubil-ity may be rejected during the drug discovery stage. This
articlesummarizes how an excipient-mixture approach can enhancethe
solubility, the in vitro dissolution, and the
bioavailabilityprofile of a low-solubility compound.
s drug development costs continue to rise, it hasbecome
increasingly important for companies to assessearly on whether a
new molecular entity (NME) will suc-ceed in clinical trials.
Analyzing the structure of a new com-pound is an especially crucial
step in the discovery stage fororally active drugs, as their
solubility and permeabilityproperties are two of the strongest
predictors of whetherPhase II (proof-of-concept) studies will
commence [1].
Companies profile NMEs so they can incorporate cer-tain
desirable characteristics into the molecule; selectlead compounds
that are likely to survive in the pipeline;
c-Kheurart_10-15_Masters 12/30/13 1:55 PM Page 10
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Tablets & Capsules January 2014 11
and recognize development risks as soon as possible [2].Key
criteria in assessing an NMEs development potentialinclude economic
factors, such as ease of manufactureand market size;
pharmacological considerations, such astherapeutic ratio, toxicity,
and how the compound inter-acts with other APIs; and physical
characteristics, such assolubility [1].
Solubility, which refers to the concentration of asolute in a
saturated solution at a defined temperature andpressure, is key to
a drug products efficiency [3]. For adrug product to exert its
therapeutic effect, it must be sol-uble in an aqueous environment.
This quality ensures thatthe API will dissolve in intestinal fluids
and provide suffi-cient concentration to induce absorption in the
GI tract[4]. The oral delivery of low-solubility drug products
isassociated with slow dissolution rates, low and
variablebioavailability, and a higher potential for food effect
[2].
Hence, API candidates with promising pharmacody-namics may be
rejected as lead molecules due to poor sol-ubility. Unfortunately,
approximately 40 percent of allNMEs exhibit this quality [5],
meaning that they are clas-sified as either Class II (low
solubility, high permeability)or Class IV (low solubility, low
permeability) in theBiopharmaceutics Classification System
(BCS).
Factors that cause poor solubility include high crys-tallinity
and hydrophobicity [2]. The latter is a character-istic more
commonly found in leads obtained via high-throughput screening
(HTS) because those NMEs tend tohave higher molecular weights than
do leads acquired dur-ing the pre-HTS era [6]. HTS allows for
exponentiallyfaster screening at a fraction of the cost of
conventionaltechniques, and it has thus become a major paradigm
ofdrug discovery [7]. As a result, new formulation strategiesare
required to achieve acceptable bioavailability.
Liquid-filled hard capsules (LFHCs) offer a platform formanaging
the successful transition from a low-solubility,to-be-abandoned
molecule to a potent bioactive drugproduct. The means to do so,
however, are restricted bythe APIs physicochemical properties,
whichaside frompoor water solubilitymay also include a low
meltingpoint (causing it to stick to tooling surfaces), a critical
sta-bility profile, and a short half-life [8].
Formulators can use a wide array of solubilizers, co-sol-vents,
surfactants, and emulsifying agents to achieve favor-able
pharmacokinetics. For instance, an APIs rate ofrelease from hard
capsules filled with semi-solid excipientscan be controlled by
using excipients with differenthydrophilic-lipophilic balance (HLB)
values, as demon-strated by an experiment in which the in vitro
release rateof salicylic acid from a mixture of lipid
excipients(Gelucire from Gattefoss) was found to be directly
pro-portional to the HLB value of the composition of the
fillmaterial [9].
Generous use of any one excipient is limited, however,by
permissible-daily-intake standards, individual solubi-lizing
capacities, and potential interactions with the cap-sule wall: The
fill material must not degrade or leakthrough the gelatin shell. So
the challenge is to find a for-
mulation approach that enables the judicious selection
ofexcipients by type and use level.
This article summarizes how an excipient-mixtureapproach was
able to enhance the solubility, in vitro dis-solution, and
bioavailability profile of a low-solubility(0.5 milligram per
milliliter (mg/mL)) BCS Class II com-pound, thereby enabling
researchers to establish a rea-sonable spread of prototype
formulations in order to con-duct in vivo studies in animals.
MethodologyStage 1: Vehicle screening studies. In the first set
of
trials, the API was dissolved in a variety of excipients
thatwere either liquid or semi-solid at ambient temperature,using
an approximate API-to-excipient ratio of 1-to-90.The solutions were
then visually evaluated for clarity andsonicated for 30 minutes to
further agitate the particles. Aclear solution was not achieved,
however, indicating thatnone of the excipients adequately dissolved
the API.Consequently, no further studies were conducted atambient
temperature.
Subsequent trials involved dissolving the API in a vari-ety of
excipients at elevated temperatures (~65C 5C)through the
application of indirect heat (using a water bathand hot plate)
accompanied by intermittent stirring. Someof the excipients were
semi-solid at room temperature butmelted at temperatures exceeding
55C. An approximateAPI-to-excipient ratio of 1-to-90also expressed
as ~1.1percent w/w APIwas again used. See Table 1 for a list ofthe
excipients evaluated at higher temperatures.
Based on initial solubility studies of the excipientpreparations
used to make self-emulsifying lipid formula-tions (SELFs),
preparations 27C, 27D, 27F, and 27H wereheated gradually from 65 to
115C. It was observed thatthe API dissolved incrementally as the
temperatureincreased. At temperatures higher than 65C, however,some
excipients degraded, so 65C became the targettemperature in further
studies.
Stage 2: A mixture approach to study solubility atelevated
temperatures. Select excipients were mixed invarious proportions
(Table 2). The API was then dis-solved in each mixture and each was
assessed to gaugesolubility improvement. Similar to the solubility
processused for individual excipients, indirect heat was appliedto
melt the excipients and/or disperse the API. A temper-ature of
approximately 65C was maintained throughoutthe evaluation process,
and the quantity of API used wasgradually increased depending on
the solubilizationcapacity of the mixture.
Stage 3: Selection of an optimal mixture. Based onthe literature
and a visual evaluation of the APIs solubilityin various excipients
and excipient mixtures, it washypothesized that a combination of
two or more selectexcipients (Imwitor 308, Gelucire 44/14, vitamin
ETPGS, hydroxypropyl beta cyclodextrin, and propyleneglycol) would
yield a formulation with the desired in vitrodissolution profile
and in vivo bioavailability characteris-tics. Among these five
excipients, Gelucire 44/14 was con-
c-Kheurart_10-15_Masters 12/30/13 1:55 PM Page 11
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sidered a key ingredient for emulsification and
potentialbioavailability enhancement. Two SELF preparations (27Fand
27H) were also selected to assess in vitro dissolution.
Stage 4: Manufacture of prototype batches. Fourexcipient
combinations (lots 1 through 4) were used to
formulate LFHC prototypes (Table 3). These prototypeswere
manufactured with the required target dose inbatches of 1,500
capsules, but the capsules were notbanded and thus not completely
sealed. The butylatedhydroxyanisole (BHA) and butylated
hydroxytoluene
12 January 2014 Tablets & Capsules
Table 1Excipients evaluated at elevated temperature
Gelucire 44/14 Crillet 1 HP Labrasol Plurol Oleique CC 497
Solutol HS 15Cremophor RH 4 Propylene glycol PEG 400 Peppermint oil
Miglyol 810
PEG 8000 Labrafil M2125 Vitamin E TPGS Cremophor ELP
Medium-chain triglyceridesSchercemol TN Labrafac CC Polysorbate 80
Macol LA 4 Gelucire 50/13
Transcutol Soybean oil Glycerin Sunflower oil Captex 355Captex
200P Capmul MCM Capmul PG-8 Bio-Soft N25-7 Neobee M-5
Lauroglycol 90 Labrafac Hydro WL 1219 Labrafac PG Miglyol 829
Softisan 645Miglyol 812 Miglyol 840 Capryol 90 Cottonseed oil
Imwitor 308
Softigen 701 Imwitor 742 Imwitor 988 Imwitor 491 Hexylene
glycolAkomed R Myvacet 9-45K S.E.L.F. 27A* S.E.L.F. 27B* S.E.L.F.
27C**
S.E.L.F. 27D** S.E.L.F. 27E** S.E.L.F. 27F** S.E.L.F. 27G*
S.E.L.F. 27H**
* Semisolid at room temperature** Liquid at room temperature
Table 2Excipient mixtures used to evaluate solubility at
elevated temperature
Serial number Excipients Proportion
1 Citric acid (1.0%) + HPBCD* (20% solution in water) 1.0 ml +
3.5 ml2 Propylene glycol + HPBCD 2.250 g + 2.250 g3 Propylene
glycol + citric acid + HPBCD 3.000 g + 0.045 g + 1.455 g4 Glycerin
+ HPBCD 3.500 g + 1.000 g5 Glycerin + citric acid + HPBCD 3.455 g +
0.045 g + 1.000 g6 Transcutol HP + HPBCD 3.500 g + 1.000 g7
Transcutol HP + citric acid + HPBCD 3.455 g + 0.04 5g + 1.000 g8
Cremophor ELP + Transcutol HP 1.000 g + 3.500 g9 Cremophor ELP +
propylene glycol 1.000 g + 3.500 g
10 Transcutol HP + propylene glycol 2.250 g + 2.250 g1 Propylene
glycol + polyethylene glycol 8000 + Transcutol HP 2.000g + 0.450 g
+ 2.000 g
12 Propylene glycol + glycerin + Transcutol HP 2.000 g + 0.750 g
+ 1.750 g13 Transcutol HP + hexylene glycol 3.000 g + 1.500 g14
Gelucire 44/14 + Transcutol HP + propylene glycol 1.500 g + 1.500 g
+ 1.500 g15 Cremophor ELP + PEG 8000 2.750 g + 1.750 g16 Cremophor
ELP + propylene glycol + HPBCD 2.000 g + 1.000 g+ 1.500 g17 Capmul
MCM + Cremophor ELP 1.000 g + 3.500 g18 Capmul MCM + Cremophor RH
40 1.500 g + 3.000 g19 Captisol + Cremophor ELP + PEG 8000 1.000 g
+ 2.750 g + 0.750 g20 Captisol + Cremophor ELP + propylene glycol
1.000 g + 2.000 g + 1.5000 g21 Cremophor ELP + propylene glycol +
Imwitor 308 1.350 g + 0.900 g + 2.250 g22 Cremophor ELP +
Transcutol HP + Imwitor 308 0.900 g + 0.450 g + 3.150 g23 Cremophor
ELP + propylene glycol + Imwitor 308 1.125 g + 0.675 g + 2.250 g24
Propylene glycol + Transcutol + Imwitor 308 0.900 g + 0.900 g +
2.700 g25 Gelucire 44/14 + propylene glycol + Imwitor 308 0.675 g +
0.675 g + 3.150 g26 Gelucire 44/14 + Cremophor ELP 2.250 g + 2.250
g27 Myvacet 9-45K + Lauroglycol + Labrasol 2.250 g + 0.450 g +
1.800 g
* HPBCD = hydroxypropyl-beta-cyclodextrin
c-Kheurart_10-15_Masters 12/30/13 1:55 PM Page 12
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14 January 2014 Tablets & Capsules
(BHT) were added as preservatives. Accelerated stabilitystudies
were then conducted on all formulations to deter-mine the
shelf-life of each drug product.
The manufacturing process involved melting theexcipients at a
temperature of ~65C and then dispersingthe API into each mixture by
stirring. The molten mix-tures were then placed into hard gelatin
capsules (Licapsfrom Capsugel). Lots 5 and 6 were manufactured by
dis-solving the API into excipient preparations 27F and
27H,respectively.
Results and discussionStage 1: Vehicle screening studies. None
of the individ-
ual excipients subjected to the screening studies achievedthe
target solubility (~200 mg/mL) at both ambient and ele-vated
temperatures. Table 4 lists which excipients displayed1)
insolubility and partial wetting properties and which were2)
partially soluble at elevated temperatures. The excipientsthat were
screened but not listed in the table were observedto have neither
wetting nor solubilization properties.
Stage 2: Mixture approach to solubility studies at ele-vated
temperatures. The API was partially soluble inmixtures 1 to 11, 14,
17, 18, 20, 21, 22, 24, and 25, asnumbered in Table 2. None of the
mixtures, however,could obtain the target solubility of ~200
mg/mL.
Stage 3: Selection of optimal mixture. The in vitrodissolution
rates in 0.1 N HCl of all six excipient mix-tures used to formulate
the LFHC prototypes are shownin Table 5 and Figure 1. Note that the
initial dissolutionof Lot 2 and Lot 4 was slower (13 percent after
10 min-utes) than those of the other prototypes (>65
percent).The different results can be attributed to the
differentproperties of the excipients and the different ratios
ofexcipients that were used. Overall, the dissolution pro-files
provide a reasonable spread of prototype formula-tions for
conducting in vivo animal studies.
Although a clear solution was not obtained, Lot 1 andLot 3
dissolved 75 percent of the API in 45 minutes,which justifies
further evaluation of both prototype for-mulations in animal
studies. No significant changes in theappearance of the capsule
shell and the contents of thecapsule were noted during accelerated
stability studies.Chemical stability was also encouraging. Finally,
no leak-age of the contents was observed, even though the cap-sules
were not sealed. Figures 2 and 3 show the acceler-ated stability
data for lots 1 and 3.
Excipient preparations 27F and 27H (lots 5 and 6)were not
considered for further assessment. They willonly be re-evaluated if
required, based on the results ofthe in vivo studies conducted
using lots 1 and 3.
Table 3Mixtures used to evaluate in vitro dissolution
(milligrams per capsule)
Gelucire 44/14 Imwitor 308 Vitamin E TPGS HPBCD Propylene glycol
BHA BHT
Lot 1 248.59 250 -- -- -- 0.1 0.5Lot 2 498.59 -- -- -- 0.1
0.5Lot 3 -- 248.59 200 -- 50 0.1 0.5Lot 4 348.59 125.00 -- 25 --
0.1 0.5
Table 4Observations during solubility studies at elevated
temperature
Insoluble with partial wetting properties Partially soluble
Gelucire 44/14, Gelucire 50/13, Polysorbate 80, Propylene
glycol, Miglyol 810, Imwitor 308, Imwitor 988,S.E.L.F. 27F, and
S.E.L.F. 27H Crillet 1 HP, Solutol HS 15, glycerin, Capryol 90,
Imwitor 491,
Imwitor 742, Labrasol, Cremophor RH 40, MCT, Capmul MCM, and
hexylene glycol.
Table 5In vitro dissolution of selected mixtures in 0.1 N HCl
(mean percentage dissolved)
10 min 20 min 30 min 45 min 60 min Infinity
Lot 1 66 102 103 104 104 104Lot 2 13 34 48 70 85 102Lot 3 83 95
99 101 102 103Lot 4 13 43 78 97 100 101S.E.L.F. 27F (Lot 5) 68 84
89 90 91 91S.E.L.F. 27H (Lot 6) 80 91 93 93 93 93
c-Kheurart_10-15_Masters 12/30/13 1:55 PM Page 14
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ConclusionGelatin LFHCs offer a simple yet effective means
of
formulating compounds with low aqueous solubility. Eventhough
complete solubilization was not achieved, the invitro dissolution
profile of a low-solubility compound wasimproved by associating the
API with an optimal mixtureof solubilizers and
bioavailability-enhancers. An excipient-mixture approach that takes
into consideration the differ-ent properties of excipients was used
to arrive at this opti-mal ratio. T&C
References1. Lipinski, CA. Reducing the investment made in
likely drug development failures. In Transforming
thePharmaceutical Industry: Adapting to Change inTechnology and
Markets. Cambridge HealthtechInstitute, Newton, MA, 2001.
2. Tong, WQ. Developability Assessment SupportingDrug Candidate
Selection [Powerpoint]. UT: UoUIntegrated Drug Development Process
Course; 2006.
3. Wiser L, Gao X, Jasti B, Li X. Solubility of pharma-ceutical
solids. In: Hu M, Li X, eds. Oral Bioavailability:Basic Principles,
Advanced Concepts, and Applications.Hoboken, NJ: John Wiley &
Sons, Inc.; 2011.
4. Cowan-Lincoln M. Improve the bioavailability ofpoorly soluble
drugs. PFQ. February/March 2012:12-14.
5. Kommuru TR, Gurley B, Khan MA, Reddy, IK. Self-emulsifying
drug delivery systems (SEDDS) of coenzymeQ10: formulation
development and bioavailability assess-ment. Int J Pharm.
2001;212(2):233-246.
6. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ.Experimental
and computational approaches to estimatesolubility and permeability
in drug discovery and develop-ment settings. Adv. Drug Deliv. Rev.
2001;46(1-3):326.
7. Keseru GM, Makara GM. Hit discovery and hit-to-lead
approaches. Drug Discov Today. 2006;11(15-16):741-748.
8. Anderson NG. Practical Process Research andDevelopment: A
Guide for Organic Chemists. 2nd ed.Oxford, UK: Elsevier, Inc.;
2012:369.
9. Howard JR, Gould PL. Drug release from ther-mosetting fatty
vehicles filled into hard gelatin capsules.Drug Dev. Ind. Pharm.
1987;13(6):10311045.
Amol Kheur is a technical project leader; Anil Kane is
executivedirector, global head of formulation sciences; Mohammad
Aleemis a senior research chemist; and Maureen McLaughlin is
asenior manager, analytical development at Patheon Pharma-ceutical
Development Services, 4721 Emperor Blvd., Suite 200,Durham, NC
27703. Tel. 919 226 3200. Website:www.patheon.com. Kiran Kumar
Tumbalam and Shiv-aprakash Poojary are former employees.
Tablets & Capsules January 2014 15
Figure 1In vitro dissolution of selected API-excipient mixtures
in
0.1 N HCl
120
100
80
60
40
20
00 10
Lot 1
Lot 4
Lot 2
S.E.L.F. 27F
Lot 3
S.E.L.F. 27H
20Time (min)
% d
isso
lved
5030 60 7040
Figure 2Lot 1 in vitro dissolution data
120
100
80
60
40
20
00 10
T = 0
T = 1 month
T = 0
T = 1
20Time (min)
% d
isso
lved
5030 60 7040
Figure 3Lot 3 in vitro dissolution data
120
100
80
60
40
20
00 10
T = 0
T = 1 month
20Time (min)
% d
isso
lved
5030 60 7040
c-Kheurart_10-15_Masters 12/30/13 1:55 PM Page 15
CoverA rapid vehicle-screening approach for formulating a
low-solubility compound into liquid-filled capsules
