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APSULES
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ormulation

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Volume 12 Number 1
January 2014

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Formulating a liquid-filled capsule

Improving capsule filling efficiency
The ABCs of roller compaction
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10 January 2014

Tablets & Capsules

formulation
A rapid vehicle-screening
approach for formulating
a low-solubility compound
into liquid-filled capsules

Amol Kheur, Anil Kane, Mohammad

Aleem, and Maureen McLaughlin

Patheon Pharmaceutical
Development Services
Kiran Kumar Tumbalam and
Shivaprakash Poojary

Formerly of Patheon

For a drug product to exert its therapeutic effect, it must be soluble in an aqueous environment. This ensures that the active
pharmaceutical ingredient (API) will provide sufficient concentration to induce gastrointestinal (GI) tract absorption. Hence,
molecules with promising pharmacodynamics yet poor solubility may be rejected during the drug discovery stage. This article
summarizes how an excipient-mixture approach can enhance
the solubility, the in vitro dissolution, and the bioavailability
profile of a low-solubility compound.

s drug development costs continue to rise, it has

become increasingly important for companies to assess
early on whether a new molecular entity (NME) will succeed in clinical trials. Analyzing the structure of a new compound is an especially crucial step in the discovery stage for
orally active drugs, as their solubility and permeability
properties are two of the strongest predictors of whether
Phase II (proof-of-concept) studies will commence [1].
Companies profile NMEs so they can incorporate certain desirable characteristics into the molecule; select
lead compounds that are likely to survive in the pipeline;

c-Kheurart_10-15_Masters 12/30/13 1:55 PM Page 11

January 2014 11

Tablets & Capsules

and recognize development risks as soon as possible [2].
Key criteria in assessing an NMEs development potential
include economic factors, such as ease of manufacture
and market size; pharmacological considerations, such as
therapeutic ratio, toxicity, and how the compound interacts with other APIs; and physical characteristics, such as
solubility [1].
Solubility, which refers to the concentration of a
solute in a saturated solution at a defined temperature and
pressure, is key to a drug products efficiency [3]. For a
drug product to exert its therapeutic effect, it must be soluble in an aqueous environment. This quality ensures that
the API will dissolve in intestinal fluids and provide sufficient concentration to induce absorption in the GI tract
[4]. The oral delivery of low-solubility drug products is
associated with slow dissolution rates, low and variable
bioavailability, and a higher potential for food effect [2].
Hence, API candidates with promising pharmacodynamics may be rejected as lead molecules due to poor solubility. Unfortunately, approximately 40 percent of all
NMEs exhibit this quality [5], meaning that they are classified as either Class II (low solubility, high permeability)
or Class IV (low solubility, low permeability) in the
Biopharmaceutics Classification System (BCS).
Factors that cause poor solubility include high crystallinity and hydrophobicity [2]. The latter is a characteristic more commonly found in leads obtained via highthroughput screening (HTS) because those NMEs tend to
have higher molecular weights than do leads acquired during the pre-HTS era [6]. HTS allows for exponentially
faster screening at a fraction of the cost of conventional
techniques, and it has thus become a major paradigm of
drug discovery [7]. As a result, new formulation strategies
are required to achieve acceptable bioavailability.
Liquid-filled hard capsules (LFHCs) offer a platform for
managing the successful transition from a low-solubility,
to-be-abandoned molecule to a potent bioactive drug
product. The means to do so, however, are restricted by
the APIs physicochemical properties, whichaside from
poor water solubilitymay also include a low melting
point (causing it to stick to tooling surfaces), a critical stability profile, and a short half-life [8].
Formulators can use a wide array of solubilizers, co-solvents, surfactants, and emulsifying agents to achieve favorable pharmacokinetics. For instance, an APIs rate of
release from hard capsules filled with semi-solid excipients
can be controlled by using excipients with different
hydrophilic-lipophilic balance (HLB) values, as demonstrated by an experiment in which the in vitro release rate
of salicylic acid from a mixture of lipid excipients
(Gelucire from Gattefoss) was found to be directly proportional to the HLB value of the composition of the fill
material [9].
Generous use of any one excipient is limited, however,
by permissible-daily-intake standards, individual solubilizing capacities, and potential interactions with the capsule wall: The fill material must not degrade or leak
through the gelatin shell. So the challenge is to find a for-

mulation approach that enables the judicious selection of

excipients by type and use level.
This article summarizes how an excipient-mixture
approach was able to enhance the solubility, in vitro dissolution, and bioavailability profile of a low-solubility
(0.5 milligram per milliliter (mg/mL)) BCS Class II compound, thereby enabling researchers to establish a reasonable spread of prototype formulations in order to conduct in vivo studies in animals.

Methodology
Stage 1: Vehicle screening studies. In the first set of
trials, the API was dissolved in a variety of excipients that
were 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 and
sonicated for 30 minutes to further agitate the particles. A
clear solution was not achieved, however, indicating that
none of the excipients adequately dissolved the API.
Consequently, no further studies were conducted at
ambient temperature.
Subsequent trials involved dissolving the API in a variety of excipients at elevated temperatures (~65C 5C)
through the application of indirect heat (using a water bath
and hot plate) accompanied by intermittent stirring. Some
of the excipients were semi-solid at room temperature but
melted at temperatures exceeding 55C. An approximate
API-to-excipient ratio of 1-to-90also expressed as ~1.1
percent w/w APIwas again used. See Table 1 for a list of
the excipients evaluated at higher temperatures.
Based on initial solubility studies of the excipient
preparations used to make self-emulsifying lipid formulations (SELFs), preparations 27C, 27D, 27F, and 27H were
heated gradually from 65 to 115C. It was observed that
the API dissolved incrementally as the temperature
increased. At temperatures higher than 65C, however,
some excipients degraded, so 65C became the target
temperature in further studies.
Stage 2: A mixture approach to study solubility at
elevated temperatures. Select excipients were mixed in
various proportions (Table 2). The API was then dissolved in each mixture and each was assessed to gauge
solubility improvement. Similar to the solubility process
used for individual excipients, indirect heat was applied
to melt the excipients and/or disperse the API. A temperature of approximately 65C was maintained throughout
the evaluation process, and the quantity of API used was
gradually increased depending on the solubilization
capacity of the mixture.
Stage 3: Selection of an optimal mixture. Based on
the literature and a visual evaluation of the APIs solubility
in various excipients and excipient mixtures, it was
hypothesized that a combination of two or more select
excipients (Imwitor 308, Gelucire 44/14, vitamin E
TPGS, hydroxypropyl beta cyclodextrin, and propylene
glycol) would yield a formulation with the desired in vitro
dissolution profile and in vivo bioavailability characteristics. Among these five excipients, Gelucire 44/14 was con-

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Tablets & Capsules

12 January 2014

sidered a key ingredient for emulsification and potential

bioavailability enhancement. Two SELF preparations (27F
and 27H) were also selected to assess in vitro dissolution.
Stage 4: Manufacture of prototype batches. Four
excipient combinations (lots 1 through 4) were used to

formulate LFHC prototypes (Table 3). These prototypes

were manufactured with the required target dose in
batches of 1,500 capsules, but the capsules were not
banded and thus not completely sealed. The butylated
hydroxyanisole (BHA) and butylated hydroxytoluene

Table 1
Excipients evaluated at elevated temperature
Gelucire 44/14
Cremophor RH 4
PEG 8000
Schercemol TN
Transcutol
Captex 200P
Lauroglycol 90
Miglyol 812
Softigen 701
Akomed R
S.E.L.F. 27D**

Crillet 1 HP
Propylene glycol
Labrafil M2125
Labrafac CC
Soybean oil
Capmul MCM
Labrafac Hydro WL 1219
Miglyol 840
Imwitor 742
Myvacet 9-45K
S.E.L.F. 27E**

Labrasol
PEG 400
Vitamin E TPGS
Polysorbate 80
Glycerin
Capmul PG-8
Labrafac PG
Capryol 90
Imwitor 988
S.E.L.F. 27A*
S.E.L.F. 27F**

Plurol Oleique CC 497

Peppermint oil
Cremophor ELP
Macol LA 4
Sunflower oil
Bio-Soft N25-7
Miglyol 829
Cottonseed oil
Imwitor 491
S.E.L.F. 27B*
S.E.L.F. 27G*

Solutol HS 15
Miglyol 810
Medium-chain triglycerides
Gelucire 50/13
Captex 355
Neobee M-5
Softisan 645
Imwitor 308
Hexylene glycol
S.E.L.F. 27C**
S.E.L.F. 27H**

* Semisolid at room temperature

** Liquid at room temperature

Table 2
Excipient mixtures used to evaluate solubility at elevated temperature
Serial number

Excipients

Proportion

1
2
3
4
5
6
7
8
9
10
1
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27

Citric acid (1.0%) + HPBCD* (20% solution in water)

Propylene glycol + HPBCD
Propylene glycol + citric acid + HPBCD
Glycerin + HPBCD
Glycerin + citric acid + HPBCD
Transcutol HP + HPBCD
Transcutol HP + citric acid + HPBCD
Cremophor ELP + Transcutol HP
Cremophor ELP + propylene glycol
Transcutol HP + propylene glycol
Propylene glycol + polyethylene glycol 8000 + Transcutol HP
Propylene glycol + glycerin + Transcutol HP
Transcutol HP + hexylene glycol
Gelucire 44/14 + Transcutol HP + propylene glycol
Cremophor ELP + PEG 8000
Cremophor ELP + propylene glycol + HPBCD
Capmul MCM + Cremophor ELP
Capmul MCM + Cremophor RH 40
Captisol + Cremophor ELP + PEG 8000
Captisol + Cremophor ELP + propylene glycol
Cremophor ELP + propylene glycol + Imwitor 308
Cremophor ELP + Transcutol HP + Imwitor 308
Cremophor ELP + propylene glycol + Imwitor 308
Propylene glycol + Transcutol + Imwitor 308
Gelucire 44/14 + propylene glycol + Imwitor 308
Gelucire 44/14 + Cremophor ELP
Myvacet 9-45K + Lauroglycol + Labrasol

1.0 ml + 3.5 ml
2.250 g + 2.250 g
3.000 g + 0.045 g + 1.455 g
3.500 g + 1.000 g
3.455 g + 0.045 g + 1.000 g
3.500 g + 1.000 g
3.455 g + 0.04 5g + 1.000 g
1.000 g + 3.500 g
1.000 g + 3.500 g
2.250 g + 2.250 g
2.000g + 0.450 g + 2.000 g
2.000 g + 0.750 g + 1.750 g
3.000 g + 1.500 g
1.500 g + 1.500 g + 1.500 g
2.750 g + 1.750 g
2.000 g + 1.000 g+ 1.500 g
1.000 g + 3.500 g
1.500 g + 3.000 g
1.000 g + 2.750 g + 0.750 g
1.000 g + 2.000 g + 1.5000 g
1.350 g + 0.900 g + 2.250 g
0.900 g + 0.450 g + 3.150 g
1.125 g + 0.675 g + 2.250 g
0.900 g + 0.900 g + 2.700 g
0.675 g + 0.675 g + 3.150 g
2.250 g + 2.250 g
2.250 g + 0.450 g + 1.800 g

* HPBCD = hydroxypropyl-beta-cyclodextrin

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Tablets & Capsules

14 January 2014

(BHT) were added as preservatives. Accelerated stability

studies were then conducted on all formulations to determine the shelf-life of each drug product.
The manufacturing process involved melting the
excipients at a temperature of ~65C and then dispersing
the API into each mixture by stirring. The molten mixtures were then placed into hard gelatin capsules (Licaps
from Capsugel). Lots 5 and 6 were manufactured by dissolving the API into excipient preparations 27F and 27H,
respectively.

Results and discussion

Stage 1: Vehicle screening studies. None of the individual excipients subjected to the screening studies achieved
the target solubility (~200 mg/mL) at both ambient and elevated temperatures. Table 4 lists which excipients displayed
1) insolubility and partial wetting properties and which were
2) partially soluble at elevated temperatures. The excipients
that were screened but not listed in the table were observed
to have neither wetting nor solubilization properties.
Stage 2: Mixture approach to solubility studies at elevated temperatures. The API was partially soluble in
mixtures 1 to 11, 14, 17, 18, 20, 21, 22, 24, and 25, as
numbered 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 vitro

dissolution rates in 0.1 N HCl of all six excipient mixtures used to formulate the LFHC prototypes are shown
in Table 5 and Figure 1. Note that the initial dissolution
of Lot 2 and Lot 4 was slower (13 percent after 10 minutes) than those of the other prototypes (>65 percent).
The different results can be attributed to the different
properties of the excipients and the different ratios of
excipients that were used. Overall, the dissolution profiles provide a reasonable spread of prototype formulations for conducting in vivo animal studies.
Although a clear solution was not obtained, Lot 1 and
Lot 3 dissolved 75 percent of the API in 45 minutes,
which justifies further evaluation of both prototype formulations in animal studies. No significant changes in the
appearance of the capsule shell and the contents of the
capsule were noted during accelerated stability studies.
Chemical stability was also encouraging. Finally, no leakage of the contents was observed, even though the capsules were not sealed. Figures 2 and 3 show the accelerated stability data for lots 1 and 3.
Excipient preparations 27F and 27H (lots 5 and 6)
were not considered for further assessment. They will
only be re-evaluated if required, based on the results of
the in vivo studies conducted using lots 1 and 3.

Table 3
Mixtures used to evaluate in vitro dissolution (milligrams per capsule)

Lot 1
Lot 2
Lot 3
Lot 4

Gelucire 44/14

Imwitor 308

Vitamin E TPGS

HPBCD

Propylene glycol

BHA

BHT

248.59
498.59
-348.59

250
-248.59
125.00

--200
--

---25

--

0.1
0.1
0.1
0.1

0.5
0.5
0.5
0.5

50
--

Table 4
Observations during solubility studies at elevated temperature
Insoluble with partial wetting properties

Partially soluble

Gelucire 44/14, Gelucire 50/13, Polysorbate 80,

S.E.L.F. 27F, and S.E.L.F. 27H

Propylene glycol, Miglyol 810, Imwitor 308, Imwitor 988,

Crillet 1 HP, Solutol HS 15, glycerin, Capryol 90, Imwitor 491,
Imwitor 742, Labrasol, Cremophor RH 40, MCT,
Capmul MCM, and hexylene glycol.

Table 5
In vitro dissolution of selected mixtures in 0.1 N HCl (mean percentage dissolved)

Lot 1
Lot 2
Lot 3
Lot 4
S.E.L.F. 27F (Lot 5)
S.E.L.F. 27H (Lot 6)

10 min

20 min

30 min

45 min

60 min

Infinity

66
13
83
13
68
80

102
34
95
43
84
91

103
48
99
78
89
93

104
70
101
97
90
93

104
85
102
100
91
93

104
102
103
101
91
93

c-Kheurart_10-15_Masters 12/30/13 1:55 PM Page 15

Tablets & Capsules

January 2014 15

Figure 1

Conclusion

60

Gelatin LFHCs offer a simple yet effective means of

formulating compounds with low aqueous solubility. Even
though complete solubilization was not achieved, the in
vitro dissolution profile of a low-solubility compound was
improved by associating the API with an optimal mixture
of solubilizers and bioavailability-enhancers. An excipientmixture approach that takes into consideration the different properties of excipients was used to arrive at this optimal ratio.
T&C

40

References

In vitro dissolution of selected API-excipient mixtures in

0.1 N HCl
120
100

% dissolved

80

20
0

10

20

30
40
Time (min)

50

60

Lot 1

Lot 2

Lot 3

Lot 4

S.E.L.F. 27F

S.E.L.F. 27H

70

Figure 2
Lot 1 in vitro dissolution data
120
100

% dissolved

80
60
40
T=0

20

T = 1 month

0
0

10

20

30
40
Time (min)

50

60

70

Figure 3
Lot 3 in vitro dissolution data

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4. Cowan-Lincoln M. Improve the bioavailability of
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6. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ.
Experimental and computational approaches to estimate
solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev. 2001;46(1-3):326.
7. Keseru GM, Makara GM. Hit discovery and hit-tolead approaches. Drug Discov Today. 2006;11(1516):741-748.
8. Anderson NG. Practical Process Research and
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Oxford, UK: Elsevier, Inc.; 2012:369.
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Drug Dev. Ind. Pharm. 1987;13(6):10311045.

120
100

% dissolved

80
60
40
T=0

20
T = 1 month

0
0

10

20

30
40
Time (min)

50

60

70

Amol Kheur is a technical project leader; Anil Kane is executive

director, global head of formulation sciences; Mohammad Aleem
is a senior research chemist; and Maureen McLaughlin is a
senior manager, analytical development at Patheon Pharmaceutical Development Services, 4721 Emperor Blvd., Suite 200,
Durham, NC 27703. Tel. 919 226 3200. Website:
www.patheon.com. Kiran Kumar Tumbalam and Shivaprakash Poojary are former employees.