Vol. 9, No.

2 2012
Drug Discovery Today: Technologies

Editors-in-Chief
Kelvin Lam – Harvard University, USA
Henk Timmerman – Vrije Universiteit, The Netherlands
DRUG DISCOVERY
TODAY
TECHNOLOGIES Formulation technologies to overcome poor drug-like properties

Optimizing the physical form –

opportunities and limitations
Stephen R. Byrn*, Jan-Olav Henck
Purdue University and SSCI, An Aptuit Company, West Lafayette, IN 47906, United States

This review addresses the question: ‘When can opti-

Section editors:
mizing the physical form rescue leads with poor drug- Max Zeller – addc GmbH, Fuellinsdorf, Switzerland.
like properties.’ This review addresses strategies invol- Tom Alfredson – Gilead Sciences, Foster City, CA, USA
ving: (1) alternate polymorphs or solvates; (2) salts; and
(3) cocrystals. Amorphous materials are also briefly the three forms of carbon: diamond, graphite and fullerenes).
Solvates/hydrates and cocrystals – these crystal forms, in
addressed. Overall, it is clear, based upon the unique
addition to containing molecules of the same given sub-
properties that a new form can provide that optimizing stance, also contain molecules of solvent or guest regularly
the solid form can rescue a drug lead. What is not incorporated into a unique structure (think of wet, setting
known or predictable is when an optimized form will be plaster: CaSO4 + 2H2O ! CaSO42H2O). Solvates include
hydrates.
found or occur. Instead, one must screen to try to find a
Salts – salts contain molecules of the same given drug sub-
‘home run’ form. stance along with counterions (salts) regularly incorporated
into a unique crystalline structure. Salts can have unique
Introduction properties and greatly enhanced aqueous solubility.
This review summarizes the unique properties that solid Amorphous forms – amorphous solids have no long-range
forms including salts, hydrates, cocrystals and amorphous order, are not crystalline, and therefore do not give a defini-
forms can have. These unique properties mean that optimiz- tive X-ray diffraction pattern. The properties of these solids
ing the solid form can in some cases rescue a drug lead. are of interest because they differ considerably from those of
However, to determine whether alteration of the solid form their crystalline counterparts.
can rescue drug leads it is important to understand different
solid forms at the fundamental level. An understanding of the The familiar example of pure carbon in its three forms –
physical form of drugs begins with the realization that most diamond (tetrahedral lattice), graphite (polyaromatic sheets)
drugs are used in crystalline form and that the arrangement of and fullerenes (polyaromatic spheres) – dramatizes the pro-
molecules in a crystal determine its physical properties. found effect that differences in crystal structure can have on
Additionally it is, of course important to realize that mate- the properties of a solid. Similar effects can apply to other
rials can crystallize in different ways. solid compounds, including drugs. Given the endless chemi-
cal variety of modern drug molecules it becomes obvious why
Polymorphs – when two crystals have the same chemical different solid-state forms can be used to optimize physical
composition but different internal structure (molecular packing) properties and rescue drug leads.
they are polymorphic modifications or polymorphs (think of Many physicochemical properties of a drug (Table 1) vary
when the solid-state structure of the substance is altered. The
*Corresponding author.: S.R. Byrn ([email protected]) practical significance of any of these differences will, of course,

1740-6749/$ ß 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ddtec.2012.03.006 e73

 Drug Discovery Today: Technologies | Formulation technologies to overcome poor drug-like properties Vol. 9, No. 2 2012

Table 1. Properties of a compound that depend on structure differences

Density Water uptake Solid-state reactivity
Hardness Optical Properties Physical and chemical stability
Cleavage Electrical Properties Dissolution rate, solubility (apparent solubility)

vary from case to case. However, it is clear that some of these 1–0.1 mg/mL depending upon dose. Of course for a low dose
advantageous properties can lead to a solid form that is easy drug poor solubility is not as much of a barrier as for high dose
to develop. drugs. The concept of maximum absorbable dose (MAD)
For example, Byrn following the prior work of Brenner captures this issue. The MAD [3] is:
showed that the hydrate/solvate form of prednisolone tert-
MAD ¼ S  Ka  SIWW  SITT
butylacetate oxidized (was chemically unstable) whereas the
anhydrous form was stable [1]. For clopidogrel, the free base is where
an oil which cannot be easily manufactured whereas the
bisulfate salt is high melting, has good flow, and is easy to  S = solubility in mg/mL.
crystallize [2].  Ka = intestinal absorption rate constant (min1).
 SIWW = small intestine water volume (mL) – about
Methods of analysis 250 mL.
The first step in understanding the role of the solid form in  SITT = small intestine transit time – about 4.5 h.
developing a drug lead is to analyze the solid form as pre-
sented/isolated. A wide range of methods of analysis are The maximum absorbable dose is directly proportional to
available for the various solid forms listed above. These solubility, meaning that only a low dose of a poorly soluble
methods are listed in Table 2. For regulatory purposes it is drug can be absorbed.
important to use these methods to verify the form present
and to insure mixtures are not present. Mixtures can com- Poor stability
plicate the setting of specifications and are usually difficult to Stability involves physical and/or chemical stability. Physical
reproducibly manufacture. instability occurs when a solid form transforms to another
solid form during storage or processing. Chemical instability
Undesirable/poor drug properties occurs when chemical bonds are broken (degradation) or
The pharmaceutical sciences literature and patents describe formed (e.g. dimerization). Chemical stability problems
poor drug properties. In the broadest sense there are a large usually occur with compounds that are intrinsically unstable
number of undesirable properties. In this section only the and contain one or more reactive groups. Physical instability
most common undesirable properties are highlighted. occurs when a solid form change (e.g. amorphous to crystal-
line) takes place.
Poor solubility
Although it is not possible to put an exact number on poor Hygroscopicity
solubility, many experts would say something in the range of Hygroscopic compounds absorb moisture from the atmo-
sphere. In extreme cases, hygroscopic compounds actually
deliquesce forming liquid solution sometimes termed ‘pud-
Table 2. Methods of analysis of solid forms dles’ or ‘puddeling’. Hygroscopicity is sometimes a precursor
Single crystal X-ray crystallography to instability because physical or chemical transformations
are often much faster in the liquid state than in the solid state.
X-ray powder diffraction
The above three problems are sometimes so serious such
Differential scanning calorimetry (DSC)
that the compound cannot be developed. In such cases,
Thermogravimetry
medicinal chemists are asked to synthesize different chemi-
Hot-stage light microscopy cals without undesirable, solubility, stability or hygroscopi-
Solubility and dissolution testing city. Alternative, another solid form can be prepared and
Particle size analysis developed as discussed below.
Infrared spectroscopy In addition to the above issues, the solid form can have
general manufacturing problems related to issues like: (1)
Raman spectroscopy
poor flow; (2) low melting point and (3) particle size. Poor
Solid-state NMR
flow often relates to the shape of particles. For example,

e74 www.drugdiscoverytoday.com
 Vol. 9, No. 2 2012 Drug Discovery Today: Technologies | Formulation technologies to overcome poor drug-like properties

needles have much poorer flow than ‘chunks’. In some cases

it is possible to overcome poor flow using milling to change Analyze Cause of Poor
the habit of the crystals or by adding flow aids as excipients. It Drug-like Properties
is not possible to change the melting point of a solid form but
it is possible to change the manufacturing method to avoid
any conditions that produce high temperatures. Particle size Hygrosco-
Solubility Stability Other
issues can cause poor flow and other difficulties in both picity
manufacturing and performance. Of course, the particle size Drug Discovery Today: Technologies
can influence the rate of dissolution. Thus, in most cases it is
Figure 1. Initial analysis of the cause of poor drug-like properties.
important to control the particle size.

Strategies to resolve poor drug properties occur when the solubility is less than 10 mg/mL. Other refer-
It is apparent that if a particular form has poor drug-like ences have stated that solubility should be 1 mg/mL or
properties the clear choice is to change forms or possibly greater.
modify the existing form. The decision is made in steps. We For stability, initial considerations require a compound
have included a flow chart for each step. that is stable enough to carry out an IND clinical trial.
Fig. 1 shows the flow chart for the first step. As shown in Ultimately, a formulation that is stable enough for a 1.5-year
this figure, analyses of the compound are carried out to half-life is generally needed to manufacture and distribute
determine its solubility, stability, hygroscopicity and other product to patients. Of course, compounds can be stored in a
relevant properties. refrigerator, however this is not desirable.
These analyses lead to one or several approaches to addres- For hygroscopicity, it is possible to manufacture materials
sing the issue. that absorb water from the atmosphere using foil-foil packa-
Problems typically occur if the aqueous solubility exhibited ging. However, a compound that absorbs water at relative
by the API means that the desired MAD cannot be achieved. humidities of less than 70% is generally considered undesir-
Interestingly, in recent years, poor solubility has often pre- able.
vented proper toxicological studies. In fact, in some cases Other problems including poor flow, low melting point
drugs have been ‘killed’ because it is not possible to achieve and particle size, can be overcome by various approaches
high enough blood levels during animal toxicology [4]. however these approaches, like packaging are expensive and
Although the cut-off for solubility varies, problems often not desirable.

Increase Apparent
Solubility

Reduce Particle New Solid

Size Form

New
Amorphous Salt Cocrystal Polymorph/
Form solvate

Drug Discovery Today: Technologies

Figure 2. Strategies to increase apparent solubility.

www.drugdiscoverytoday.com e75
 Drug Discovery Today: Technologies | Formulation technologies to overcome poor drug-like properties Vol. 9, No. 2 2012

The best salt form of each compound is remade at the 10–

20 g scale. Then, a polymorph screen on each scaled-up salt is
Improve Stability
Reduce Hygroscopicity performed.

Cocrystal screen
Experiments are typically carried out using 15–25 different
New Solid guests, with different solvents or solvent mixtures, different
Form temperatures, and different types of crystallization techni-
ques. The guests are usually selected from the GRAS list of
pharmaceutically acceptable compounds having appropriate
structure for cocrystal formation. The structure and proper-
ties of the drug substance is analyzed and used for selection of
guests providing the highest probability of successful cocrys-
Salt Cocrystal tallization. Solids are analyzed by X-ray powder diffraction,
and/or optical microscopy to determine if a cocrystal was
been produced. If cocrystals are found, up to three will be
Drug Discovery Today: Technologies selected for production at larger scale. Cocrystals which are
Figure 3. Strategies to improve stability or reduce hygroscopicity.
successfully produced are characterized by applying at least
two orthogonal methods from the following list: X-ray dif-
fraction analysis, DSC, TG, TG-IR, Raman spectroscopy, hot-
stage microscopy, NMR spectroscopy and dynamic vapor
Solubility problems of the original solid form can be sorption.
addressed in two ways as shown in Fig. 2. First, reduction
in particle size can be attempted. For example, the solid can Polymorph screen
be micronized or milled with surfactants. In extreme cases, If possible, Hot-stage microscopy is used to guide the screen-
the solid can be wet milled with a surface modifier to make ing experiments and to obtain preliminary information
nanocrystals. Approaches like this have been successful for about polymorphism. Analysis is performed during heating
fenofibrate [5]. (and cooling) by visual inspection for evidence of phase
Alternatively, a new solid form can be prepared. For these transitions (e.g. a melt (if crystalline), solvent volatilization,
studies, four screens are usually performed: (1) amorphous sublimation) and if decomposition occurs at the melt. Obser-
screen, (2) cocrystal screen, (3) salt screen and (4) polymorph vations are also made on introduction of two to three differ-
screen. Often a combination high throughput screening and ent solvents (including water) to assess dissolution and
manual screening is used for each of the screens. Experience changes in morphology, if possible. Any solids generated
indicates that high throughput screening alone is not suffi- are analyzed by XRPD, infrared (IR) or Raman spectroscopy,
cient to find all of the relevant forms (Fig. 3). if possible, to provide reference data for comparison with
materials generated during this study.
Amorphous screen Solvents and solvent mixtures are chosen based on these
An amorphous screen involves synthesizing the amorphous factors:
mater in different ways including melt quench and rapid
evaporation. An amorphous screen also typically involves fast  Known or determined solubilities of drug substance
evaporation of drug polymer solutions to determine if an (Table 1).
amorphous dispersion is produced. The best amorphous form  Solvents spanning a wide range of polarities including
produced is then scaled up often using spray-drying or melt those used for the manufacturing process.
extrusion. The scaled-up materials are further investigated for  Solvents having a variety of structural functionalities.
their properties.  Water or a water-containing solvent mixtures are included.

Salt screen Then solid samples are generated under a wide variety of
A typical salt screen involves preparing several salts of each experimental conditions. Experiments are performed by eva-
compound in one or two ways. Perform abbreviated poly- poration and cooling from solution, when solubility permits.
morph screen (e.g. about ten crystallizations) on each com- The particular combination of methods used should be deter-
pound. Then, solubility and/or hygroscopicity measurements mined based on the properties of the drug substance. Infor-
are carried out on each viable crystalline material. The mation obtained from experiments described above will be
best candidates are reprepared for additional evaluation. used to guide selection of procedures to prepare solids under

e76 www.drugdiscoverytoday.com
 Vol. 9, No. 2 2012 Drug Discovery Today: Technologies | Formulation technologies to overcome poor drug-like properties

Continue preparation attempts

Does the form
have acceptable No
solubility?
Yes
Unacceptable
Does the Yes
Form absorb
water under
humidity stress? No
Unacceptable
Does the No
form have
acceptable
Yes
stability?

FINAL
CANDIDATE

Drug Discovery Today: Technologies

Figure 4. Simple flow chart for form selection.

kinetic conditions. Typically, rapid cooling and precipitation dissolution conditions that mimic the blood levels. Of parti-
by addition of solutions to antisolvents will be used. Samples cular interest is finding dissolution conditions that gives the
are also be generated in the absence of solvent. All samples are same rank order of dissolution rate as is seen in the blood
analyzed by XRPD. levels of animals. If such a dissolution medium can be found,
It is important to realize that all of the screening outlined then this constitutes a crude IVIVC (in vitro in vivo correlation)
may not produce a form with improved properties. which is typically called an IVIVR (in vitro in vivo relationship).
The medium discovered can then be used to screen other
formulations and guide future formulation design. For exam-
Selection of form and formulation
ple, in a recent study in our laboratory, the parent drug in
The forms produced by the various screens need to be eval-
polymorph 2 was compared to the besylate salt and an amor-
uated and the best form for development needs to be selected.
phous dispersion. A crude rank order correlation was found in
Form selection is a broad topic and will not be repeated here.
0.1N HCl. This dissolution test was then used to screen addi-
However, it is appropriate to show one flow chart to describe a
tional formulations including micronized formulations. This
generic approach to form selection (Fig. 4).
test was also used to determine rates of crystallization of the
As shown in the flow chart, first, the solubility of the
amorphous dispersion in various toxicology vehicles. The
candidate forms is determined. It is often easiest to fill 25–
availability of this test accelerated formulation studies.
50 mg of the candidate form in a capsule and test in a
dissolution apparatus using 0.1N HCl to simulate dissolution
in the stomach. The dissolution rate is most conveniently
Cases where an optimized form resulted in marketing
followed using a UV probe for continuous monitoring. Based
of a new medicine
on this test, two or more soluble forms are selected for further
Several cases are know where an the solid form was optimized
analysis in a hygroscopicity test. Often it is easiest to use a
to facilitate marketing or speed development.
moisture balance to determine the moisture sorption profile.
For clopidogrel the resolved d-isomer was an oil and was
Finally, the chemical and physical stability of the form is
virtually impossible to manufacture. During a salt screen an
addressed using high temperature forced degradation condi-
attempt was made to form the sulfate salt of clopidogrel,
tions. One approach involves using variable temperature X-
however, instead the bisulfate salt crystallized. It was only
ray to monitor changes that may occur at 808C. Based on
after the discovery of this bisulfate salt that marketing was
these tests, it is possible to determine whether an optimized
possible. This salt has been termed a ‘home run’ salt because
physical form can have acceptable drug-like properties.
of its physical properties which allow easy manufacture [2].
For paroxetine hydrochloride, the original form was hygro-
IVIVR and animal pharmacokinetics studies scopic and difficult to manufacture. It was only after the
At this stage of development it may be useful to determine the hemihydrate form was discovered that Paxil was marketed.
pharmacokinetics of two or three candidate forms, if avail- It is interesting to note that Paxil was introduced to the
able, in animals. The blood levels are then used to find market after the chemical substance patent expired [6].

www.drugdiscoverytoday.com e77
 Drug Discovery Today: Technologies | Formulation technologies to overcome poor drug-like properties Vol. 9, No. 2 2012

For beclomethasone, particle growth was noted in the the solid form allowed manufacture of tablets. Likewise,
chlorofluorocarbon metered dose inhaler which was under optimizing the solid form of prednisolone tert-butylacetate
development several years ago. Once it was discovered that led to an improvement in stability. Finally, optimizing the
the particle growth was due to formation of a solvate with the solid form of paroxetine hydrochloride led to a nonhygro-
chlorofluorocarbon propellant a new form was introduced – scopic solid that could be easily manufactured.
the chlorofluorocarbon solvate with the proper particle size. The limitations of optimizing the form are not normally
Because the solvate was already formed, particle growth documented because the undesirable form is present and
ceased to be a problem [7]. there is no reason to report it in the literature. Never-the-less
For amlodipine, the original maleate salt reacted with the solid-state chemists know of many cases where extensive
amine group of amlodipine to form a biologically active screening efforts never produced an optimized form. This
degradation product. Salt screening led to the discovery of is because the formation of a ‘home run’ form is not pre-
a new salt, the besylate salt. This salt did not degrade. This dictable.
new salt became one of the most effective drugs to reduce
blood pressure – Norvasc [8]. References
For valproic acid, the original options for product devel- 1 Byrn, S.R. et al. (1988) The crystal structure, solid state NMR spectra, and
oxygen reactivity of five crystal forms of prednisolone tert-butylacetate. J.
opment were: (1) hygroscopic sodium valproate and (2)
Am. Chem. Soc. 110, 1609–1610
liquid valproic acid. Once divalproex sodium was discovered 2 Badorc, A., Frehel, D. (1989) Dextro rotatory enantiomer of methyl alpha 5
by mixing a 1:1 molar ratio of liquid valproic acid with (4,5,6,7 tetrahydro (3,2-c) thieno pyridyl) (2-chlorophenyl) acetate and the
pharmaceutical compositions containing it. USP4847265
hygroscopic sodium valproate a free flowing solid with a
3 Hilgers Allen, R. et al. (2003) In vitro testing of drug absorption for drug
melting point of over 1008C was available. This solid form ‘developability’ assessment: forming an interface between in vitro
was developed as a useful anticonvulsant – Depakote [9]. preclinical data and clinical outcome. Pharm. Res. 20, 1149–1155
This brief list is only aimed at presenting some examples of 4 Palucki, M. et al. (2010) Strategies at the interface of drug discovery and
development: early optimization of the solid state phase and preclinical
how optimizing the solid form has contributed positively to toxicology formulation for potential drug candidates. J. Med. Chem. 53,
drug development. 5897–5905
5 Hanafy, A. et al. (2007) Pharmacokinetic evaluation of oral fenofibrate
nanosuspensions and SLN in comparison to conventional suspensions of
Conclusion
micronized drug. Adv. Drug Deliv. Rev. 59, 419–426
It is clear from this review that optimizing the physical form 6 Barnes, R.D. et al. (1988) Antidepressant crystalline paroxetine
can lead to a material which is easy to develop. In two cases, hydrochloride hemihydrate. USP4721723
7 Finckenor, L.E. (1980) Beclomethasone dipropionate-hexane solvate and
clopidogrel and valproic acid, the optimized form was a solid
aerosols prepared therefrom. USP4225597
that was easy to handle and manufacture. The starting mate- 8 Davison, E., Wells, J.I. (1989) Pharmaceutical acceptable salts. USP4879303
rial in both cases was an oil or liquid. Obviously, optimizing 9 Meade, E. (1993) Sodium hydrogen divalproate oligomer. USP5212326

e78 www.drugdiscoverytoday.com