Seqens eBook - 30

SOLUBILITY

*

Secondly, even at this early stage, solubility will be used as one of

buffers are typically simple inorganic or organic systems, and they permit

the many parameters relevant for compound optimization. The

investigations of pH-dependent solubility of the compound. The solubility

final goal should be envisaged to deliver compounds with sufficient

of different salt forms can be initially assessed. As an example, for a weak

solubility to realize high bioavailability and to simplify formulation

base in the most acidic parts of the GI tract (ie, the stomach), conversion of

development and clinical progression.

the parent form to the corresponding hydrochloride salt may take place.

From a technical standpoint, realizing the required throughput to fulfill

Accordingly, solubility, as measured in the thermodynamic assay, will refer

both objectives requires a high degree of automation. The key to this and

to the salt form and not to the parent-and this information will be the

many other assay formats is provided by using pre-dissolved compounds.

physiologically relevant.

Typically, 10-mmol solutions in DMSO are utilized. This avoids handling
of the solid material which might not always be crystalline but could be
oily, sticky, or highly electrostatic. Instead of weighing the compounds,
compound handling can be carried out by simple volumetric dispensing,

Application of Biopharmaceutical
Solubility Approaches

ie, pipetting steps. Accordingly, it becomes feasible to implement solubility

As the GI tract is a complicated biological system,39,40 even the

determinations on robotic systems which carry out manipulation such

aforementioned approaches to determining pH-dependent solubility do

as volumetric dispensing, compound precipitation, and solid-liquid

not provide the complete picture of solubility behavior that will underpin

phase separation by filtration or centrifugation. Typically, these liquid

drug absorption. As a prerequisite to ensuring adequate bioavailability of

handling systems which carry out the volumetric dispensing and related

a research compound, the prediction of drug absorption becomes critical

activities can be combined with highly sensitive analytical systems, eg,

during late stage preclinical research in combination with formulation

high-performance liquid chromatography or ultra-performance liquid

development as part of pharmaceutical development. At this stage,

chromatography utilizing generic methodologies and can be applied

further parameters influencing solubility need to be assessed. As a starting

to automated solubility assessments with throughputs of 10 to 100

point, the influence of bile salts on drug solubility must be assessed. The

compounds per day.32-36

best way to obtain this information would be using human GI-media in ex

However, one has to bear in mind that this type of kinetic solubility does
not answer the question, "to what extent does my compound dissolve?"
Instead, this type of kinetic solubility provides the answer to the related
question, "to what extent does my compound precipitate?" As most drugs
are intended for oral administration, the first question is more relevant

vivo settings.41 However, this approach is not practical for routine research
and development. A much more practical way to investigate the impact
of bile salts on solubility is provided by the use of biorelevant dissolution
media, which also can be easily utilized for thermodynamic solubility
determinations. Biorelevant dissolution media such as FaSSIF (fasted

during later research phases. The key differentiating point between kinetic

state simulated intestinal fluid), FeSSIF (fed state simulated intestinal

solubility-which is obtained using the pre-dissolved compound-

fluid), FaSGF (fasted state simulated gastric fluid), and FeSGF (fed state

and thermodynamic solubility-which is obtained using the solid

simulated gastric fluid) mimic the effect of bile salts, pH, ionic strength,

compound-is given by the fact the kinetic solubility will refer in many

as well as osmolarity of human GI fluids.42 When such biorelevant media

cases to the amorphous phase. In a kinetic solubility assay, the compound

have been introduced, preparation of these systems was often a laborious

will have only very limited time to precipitate out and accordingly will

procedure. However, due to the availability of commercial ready-to-use

be mainly amorphous in nature. As a consequence, solubility will be

kits, preparation of the media has been simplified and measurements

significantly enhanced compared to thermodynamic solubility (which

of solubility in these media can be performed with throughput of 10 to

typically utilizes the crystalline phase).37

100 compounds per day.43 For many compounds, a significant increase in

The main-and in many cases only-difference between kinetic and
thermodynamic solubility assays is the usage of a solid compound
instead of DMSO stock solutions. Handling steps for the solid materials
are difficult to automate and typically become more labor-intensive and
usually constrain the throughput of thermodynamic solubility assays.

solubility is seen due to the presence of bile salts. This especially holds
true for lipophilic and basic moieties, where increases in solubility can be
up to 1 or 2 orders of magnitude. Usage of biorelevant media to determine
thermodynamic solubility allows the generation of physiologically
relevant data, but also allows the initial assessment of potential food

Importantly, at this stage information on solubility becomes available

effects (FaSSIF vs. FeSSIF solubility).

for the first time with related information on solid state characteristics

At this stage of a project, further physicochemical characterization

allowing solubility optimization strategies to commence.37,38

of research compounds is carried out for a very limited number of

An assessment of solubility by the aforementioned kinetic or

candidates and focus on intrinsic or apparent dissolution and the effect

thermodynamic solubility assays is limited to generic conditions such

of particle size. Technical feasibility of these investigations has been

as one pre-defined buffer system, typically at neutral pH. To get a

facilitated during the last decade by the development of mini-dissolution

physiologically more relevant understanding-especially for orally

apparatus and particle size determination using image analysis,44,45 which

administered drugs-thermodynamic solubility is measured using

provides important information using a few milligrams of the compound.

biorelevant conditions simulating the prevailing conditions within the

These miniaturized approaches allow the assessment of both solubility

gastrointestinal (GI) tract. Initially, this is conducted using different

and dissolution as part of pre-formulation activities, ie, salt selection,

buffers simulating the different pH conditions in the GI tract. These

polymorphic form selection, and the effect of particle size reduction.

Pharmaceutical Outsourcing |

30

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Seqens eBook

Table of Contents for the Digital Edition of Seqens eBook

Contents
Seqens eBook - 1
Seqens eBook - Contents
Seqens eBook - 3
Seqens eBook - 4
Seqens eBook - 5
Seqens eBook - 6
Seqens eBook - 7
Seqens eBook - 8
Seqens eBook - 9
Seqens eBook - 10
Seqens eBook - 11
Seqens eBook - 12
Seqens eBook - 13
Seqens eBook - 14
Seqens eBook - 15
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Seqens eBook - 17
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Seqens eBook - 20
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Seqens eBook - 29
Seqens eBook - 30
Seqens eBook - 31
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