PHARMACEUTICAL TECHNOLOG
e
d
tra
STE
,2 YA
MIKE
Chemical and Pharmaceutical Development, Johnson & Johnson, Beerse, Belgium
Laboratory of ttingham,
NG7 2RD, Uni
4School of Che
Received 31 J
Published onl
is often confounded by their poor water solubility and the chemically allowed space of the drug target.
1,3 -
r
r
ts
e-
to
r
g
of
medicinal chemistry, pharmaceutical scientists can
2010 Wiley-Liss, Inc. and the American Pharmacists Associationwhich impacts a number of derivative properties
including poor dissolution rate.1,2 Inadequate solu-
bility or dissolution rate can significantly reduce both
the rate and extent of drug absorption deleteriously
affecting oral bioavailability. Several factors rooted
As reviewed by Lipinski, high throughput screen
ing has tended to select for compounds with lowe
water-solubilities, higher lipophilicities and highe
molecular weights. Furthermore, many drug targe
have structure-activity relationship (SAR) requir
ments that do not overlap with properties known
provide for good oral bioavailability resulting in poo
develop-ability and high attrition.4,5While expandin
the chemical space of the target is the purview
Correspondence to: Ilse Weuts (Telephone: þ32-14-608205;
Fax: 32-14-607083; E-mail: iweuts@its.jnj.com)
Journal of Pharmaceutical Sciences, Vol. 100, 260–274 (2011)phous form, a study of binary drug/carrier cast films and the evaluation of a powder of the drug
and polymer processed in a manner relevant to the intended final dosage form. A variety of
thermoanalytical, spectroscopic, and spectrophotometric approaches were applied to study the
prepared materials. The data suggest a correlation between the glass forming ability and
stability of the amorphous drug and the nature of the final formulation. Cast films can provide
early information onmiscibility and stabilization and assessment of processed powders can help
define requirements and identify issues with potential final formulations.
2010 Wiley-Liss, Inc.
and the American Pharmacists Association J Pharm Sci 100:260–274, 2011
Keywords: solid dispersion; characterization; amorphous; etravirine; HPMC
INTRODUCTION
The development of new pharmaceutical agents
in contemporary drug pipelines are thought to
contribute to this overall decrease in drugability
including the manner in which drugs are discovered260 JOURNABiophysics and Surface Analysis, School of Pharmacy, University of Nottingham, University Park, No
ted Kingdom
mical Sciences and Pharmacy, University of East Anglia, Norwich, United Kingdom
anuary 2010; revised 23 April 2010; accepted 26 April 2010
ine 22 June 2010 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.22242
ABSTRACT: Solid dispersion technology represents an enabling approach to formulate poorly
water-soluble drugs.While providing for a potentially increased oral bioavailability secondary to
an increased drug dissolution rate, amorphous dispersions can be limited by their physical
stability. The ability to assess formulation risk in this regard early in development programs can
not only help in guiding development strategies but can also point to critical design elements in
the configuration of the dosage form. Based on experience with a recently approved solid
dispersion-based product, Intelence1 (etravirine), a three part strategy is suggested to predict
early formulate-ability of these systems. The components include an assessment of the amor-3velopment, Johnson & Johnson Pharmaceutical R&D, LLC, Raritan, New Jersey 088692Analytical DePhysicochemical Properties of th
and Spray Dried Powders to Pre
Success for Solid Dispersions: E
ILSE WEUTS,1 FREDERIC VAN DYCKE,1 JODY VOORSPOELS,1
MARCUS E. BREWSTER,1 DAWEI XU,2 BRIGITTE SEGMULLER
MARTYN C. DAVIES,3 SHENG QI,4 DUNCAN Q.M. CRAIG,4
1L OF PHARMACEUTICAL SCIENCES, VOL. 100, NO. 1, JANUARYY
Amorphous Drug, Cast Films,
ict Formulation Probability of
virine
VE DE CORT,1 SIGRID STOKBROEKX,1 RUUD LEEMANS,1
TSZ A. TURNER,3 CLIVE J. ROBERTS,3
READING42011

contribute to enlarging the oral drug bioavailability
space through the use of technologies that increase
apparent solubility and dissolution rate. A number
of approaches are available for increasing the
formulate-ability of BCS Class II compounds includ-
ing but not limited to complexation, micronization or
nanonization, use of cosolvents and structured lipid
systems.6–8 Solid amorphous dispersions provide a
unique opportunity in this regard.9–11 While theore-
tically of benefit in any number of situations, the
substance for 3 h at
1968C. Other methods such
as spray drying, freeze drying, and ball milling
were unsuccessful in generating stable amorphous
etravirine (data not shown). Stability was assessed
using FT-IR as described in the literature.16
Film Casting
A screening study found two useful solvent mixtures
including dichloromethane (DCM)-ethanol (80:20)
and various compositions of dimethylformamide
(DMF)-methanol (80:20, 50:50, and 40:60). Drug
and polymer (HPMC) were dissolved in the solvent
mixture of interest and the solutions were filtered and
PREDICTION OF FORMULATION PROBABILITY OF SUCCESS FOR SOLID DISPERSIONS 261physical instability of solid amorphous dispersions
often conspires to limit their usefulness. Early
assessments of factors likely to impact on the
applicability of a dispersion based approach such as
stability, are important components in any develop-
ment program centered around such a formulation
concept. We suggest herein a three pronged approach
for assessing dispersion fitness using the recently
approved drug, Intelence1 (etravirine) as an illus-
trative example.
Etravirine (Fig. 1) is a novel second generation non-
nucleoside reverse transcriptase inhibitor (NNRTI)
which acts by molecularly blocking the viral reverse
transcriptase enzyme. It achieves this by preventing
the enzyme from converting its genetic material
(RNA) into proviral DNA and thus preventing
incorporation of the viral genome into the human
host cell.12,13 The physicochemical properties of
etravirine are challenging with regard to dosage
form configuration as indicated in Table 1. A variety
of technologies were screened to optimize bioavail-
ability, however most did not add significant value.
For example, oral dosing of a nanosuspension
resulted in negligible blood levels in dog. The best
enhancement of GI uptake was provided by systems
based on an amorphous drug substance and specifi-
cally, amorphous dispersions of the compound in a
glassy carrier.9–11,14,15
These initial screening elements were the inputs
for a development program to fabricate a viable
formulation for etravirine. In devising this program,
factors thought to contribute to, or detract from
success were posited. The philosophy adopted
included (1) a study of the pure amorphous drug
phase, (2) an evaluation of cast films of the drug and a
glassy polymer (HPMC), and (3) an assessment
Figure 1. Chemical structure of etravirine.DOI 10.1002/jps JOpowder X-ray diffraction (XRD), infrared spectro-
scopy (IR), differential scanning calorimetry (DSC),
modulated temperature differential scanning calori-
metry (M-DSC) and solid state nuclear magnetic
resonance (SS-NMR). Imaging techniques such as
field emission gun-environmental scanning electron
microscopy (FEG-ESEM) and atomic force micro-
scopy (AFM)21–23 allowed the spatial assessment of
pharmaceutical formulations with resolution up to
the nanometer scale.
EXPERIMENTAL
Materials
Etravirine (Fig. 1) was obtained from Janssen
Pharmaceutica (Beerse, Belgium). The hydroxypro-
pylmethyl cellulose (HPMC) was 2910 grade with a
viscosity of 5mPa s and was purchased from Dow
Chemical (Plaquemine, LA). Amorphous etravirine
was prepared by cryomilling the crystalline drugof powders prepared using scaled-down processes
simulating those likely to apply to the finished dosage
form. Thus, this communication examines the proper-
ties of amorphous etravirine,16 the characteristics of
solvent cast films containing the drug and HPMC and
assessments of the physical state of the drug and its
miscibility with the polymer as a function of drug/
polymer ratio in spray dried powders.15,17–20 These
assessments required a number of appropriate
and complementary analytical methods such as
Table 1. Physicochemical and Solubility Properties of
Etravirine
Property Value
Molecular weight (g/mol) 435
Molecular formula C20H15BrN6O
Melting point 2608C (dec.)
logp >5
pKa (base) <3
S (water) 1mg/mL
S (0.1NHCl) 1mg/mL
S (PEG400) 74mg/mLURNAL OF PHARMACEUTICAL SCIENCES, VOL. 100, NO. 1, JANUARY 2011