Pharmaceutical preformulation · 2018-12-31 · Preformulation The objective of the Preformulation...

Pharmaceutical

preformulation

Formulation is the process of developing a drug candidate

into a drug product.

Preformulation as the name suggests is a stage that must be

undertaken before the formulation-proper can begin.

Preformulation

Preformulation is an investigation of physical and chemical

properties of a drug substance alone and when combined with

excipients.

Preformulation

The objective of the Preformulation studies are:

1. To establish the physical chemical properties of the new

drug entity

2. To determine the drug kinetics and stability.

3. To establish the drug compatibility with common

excipients

Information gained in this stage will be useful in the

development of a dosage form that is bioavailable, stable

and can be mass produced.

1. Organoleptic properties

2. Solubility, dissolution rate and partitioning.

3. Bulk properties:

Particle size

Crystallinity and polymorphism (solid state

properties)

Hygroscopicity

Density

Flow and compression properties

4. Stability and compatibility studies.

A preformulation program should generally begin with the

description of the drug substance.

Color, odor and taste of the new drug must be recorded.

Organoleptic characterization affects the different

formulation decisions that have to be made in later

stages. Examples in next slide.

Examples:

– If taste is considered to be unpalatable, a less soluble

form of the drug (salt or prodrug) could be

considered.

– Unacceptable odor or taste may force the formulator

to use flavoring agents or coat the final product.

– Unsightly or variable color may force the formulator to

use coloring agents or coat the final product.

– If the material is irritating to the skin or causing

sneezing, appropriate procedures for material

handling and personnel protection can be

developed.

Saturation solubility: is the maximum concentration of a solution

which may be prepared at a given temperature.

Knowledge of solubility is important for the manufacturing of

injectable solutions or other solution dosage forms.

Knowledge of solubility is also important for the therapeutic

outcome: no drug will reach its ultimate therapeutic target

without first being in solution.

It has been estimated that historically, up to 40% drug

candidates have been abandoned because of poor aqueous

solubility.

Solubility

Importance of solubility for oral dosage forms

The bioavailability of an orally-administered drug depends primarily on its

solubility in the GI tract and its permeability across cell membranes (i.e.

absorption).

In order to be absorbed a drug must be present in the GI fluids in a

dissolved form.

How to determine solubility?

Solubility test:

1. Excess of API in 100 mL of solvent at constant temperature (e.g. 37 °C) is agitated for a sufficient length of time (in a closed

appropriate container).

2. Samples are withdrawn as a function of time and clarified by

filtration or centrifugation and assayed using a detection

techniques (e.g. HPLC or UV).

3. A plateau concentration, corresponding to the saturation

solubility, is found.

Solubility

Solubility

Preformulation solubility studies focus on the drug-solvent

systems that could be encountered during the development

and use of a drug product: solubility values that are of special

importance in early development include those in distilled

water, 0.9% NaCl, 0.1 M HCl and 0.1 M NaOH, all at room

temperature as well as SGF and SIF at 37oC.

Solubility studies should have all factors defined including pH,

temperature, ionic strength and buffer concentrations.

Therefore, preformulation solubility studies usually involve also

pH-solubility profile, pKa determination and temperature

dependence.

How to determine solubility?

Early determination of solubility gives a good indicator about

the ease of formulation of a drug candidate:

For a final product, assuming oral delivery in a solid form, solubility of

the drug above 10 mg mL-1 is preferable, to prevent bioavailability

problems.

If needed, different mechanisms to enhance solubility may be

investigated, including:

• Micellar solubilization/ addition of surfactants

• Cyclodextrin complexation

• Use of co-solvent systems

• pH adjustment (acidic/basic drugs)

Solubility

Dissolution

Dissolution rate: the rate at which the material dissolves.

Dissolution is partially determined by solubility: drugs with low

solubility tend to have low dissolution rate and vice versa.

Similarly to solubility, dissolution rate can effect in vivo

bioavailability of drugs:

For orally delivered drugs, dissolution rate determines (to

some extent) how quickly the drug will appear in blood

stream.

Dissolution

Solid

dru

g Solution

Concentration = saturation solubility

Diffusion layer

Dissolution

How to determine dissolution rate of a drug?

Compressing the drug (API) into a compact disk and testing its dissolution

in an appropriate dissolution apparatus.

Such dissolution apparatus is different from those used for testing final

dosage forms (i.e. tablets or capsules – studied later on in the course).

http://www.just.edu.jo/~sfg/Preformulation_files/slide0038_image030.jpg

Dissolution

No solute has complete affinity for either a hydrophilic or

lipophilic phase.

In the context of preformulation, it is important to know early in

the drug development stage how a molecule will distribute

between aqueous and fatty environments.

Partition coefficient is an indication of lipophilicity which

affects permeability.

Partitioning

Partitioning

The octanol/water partition coefficient

P =𝐶𝑜

𝐶𝑤

Log P < 1 Low Permeability.

Log P 1-2 Relatively permeable.

Log P > 2 Highly permeable.

This can give an indication of the drug’s ability to diffuse

across cell membranes in vivo.

Partitioning

The most common method for determining partition and

distribution coefficients is the shake flask method.

In this technique:

The drug is shaken between octanol and water layers.

Then aliquots from the two phases are taken and

analyzed for the drug content.

The values of the partition coefficient obtained from this

type of experiments is affected by temperature, pH and

buffer ions.

1. Particle size.

2. Crystallinity and polymorphism (solid state

properties).

3. Hygroscopicity.

4. Density.

5. Flow and compression properties.

Bulk properties

Importance:

Physical stability of suspensions and emulsions.

Flow properties (e.g. for solid dosage forms).

Dissolution rate.

Main methods of analysis:

Sieve method

Microscopy

Laser diffractometers.

Particle size

Solid state properties

Solid particles are made up of molecules, atoms or ions that

are held in close proximity to each other.

Solid may be crystalline or amorphous.

The crystallinity of a drug substance can affect many aspects

of formulation, processing, as well as in vivo behavior.

Hence, it must be well characterized during the

preformulation stage.

Solid state properties Crystalline state

Crystalline materials are those in which the units (i.e. molecules, ions

or atoms) are packed in a defined order, and this order repeats over

and over again throughout the particle of solid.

The molecules of a crystalline solid are arranged in repetitious three-

dimensional lattice units.

These three dimensional lattice units may assume different shapes: Cubic as in sodium chloride

Tetragonal as in urea

Hexagonal as in iodoform

Rhombic as in iodine

Monoclinic as in sucrose

Triclinic as in boric acid


Crystalline state

Shapes of different lattice units

Crystalline solids show definite melting points, passing rather

sharply from the solid to the liquid state.


Polymorphism

Some materials may exist in more than one crystalline form.

Polymorphism is the property of having more than one

crystalline form.

These different crystalline forms of the same material are called

polymorphs.

Number of possible polymorphs ≥2

Example of polymorphism is carbon than can exist both as diamond and graphite.

Solid state properties Polymorphism - example

1. The molecules in (a) are more distant than those in (b).

it is likely that (a) is a less dense solid than (b)

2. It looks that it would be easier to physically pull a

molecule off structure in (a) than in (b), as the

molecules in (b) are more interlinked into the structure.

It is likely that:

(a) has a lower melting point than (b); (a) might

dissolve more easily than (b)

3. If pressure was applied it appears that (a) would

break easily, as there are natural break lines, whereas

(b) does not seem to have obvious break lines.

milling and compaction properties of the two forms

differ.


Key concept: different polymorphs have different physical properties (e.g. melting points, density, hardness, and solubilities).

These properties are very important in pharmaceutical processes, including dissolution and formulation.

Generally there is a correlation between solubility and melting point

high melting point = strong lattice = hard to remove molecules = low dissolution rate

Polymorphism


Polymorphism

Comparison of mean blood serum levels obtained with chloramphenicol

palmitate suspensions containing varying ratios of alpha and beta polymorphs, following

single oral. Percentage polymorph beta in the suspension. (Aulton’s Pharmaceutics, 4th

edition)


Polymorphism – stability

Given a compound that exhibits polymorphism, only one of the

forms will be the most thermodynamically stable.

All the other less stable forms are called metastable.

Transformation of the metastable forms in the most stable form

can occur (for example over long storage).


Polymorphism - preformulation

Selection of the most suitable polymorphic form of a given compound is

done in the Preformulation stage.

Ideally, the best polymorphic form should have the following

characteristics:

be the stable form (rather than metastable forms).

be easy to be processed into a dosage form

give good bioavailability

The polymorphic form that is thought to give the best compromise

between these characteristics will be chosen to be formulated into a

dosage form.

Solid state properties Polymorphism - preformulation

During preformulation, different polymorphs of the same drug

are produced and then characterized.

Characterization of these polymorphic forms involves:

1. identification of the different polymorphs;

2. quantitative analysis of the physicochemical properties of the

different polymorphs (examples: solubility, dissolution rate,

flowability, compressibility etc.).

According to these data, the most suitable polymorphic form is

selected.

Solid state properties Polymorphism - preformulation

Identification of polymorphs can be carried out either by:

1. X-ray powder diffraction (XRPD)

It is a technique in in which the pattern produced by the diffraction of X

rays through the closely spaced lattice of atoms in a crystal is recorded

and then analyzed. Each form shows a characteristic diffraction pattern.


Polymorphism – preformulation

2. Differential Scanning calorimetry (DSC)

It allows to differentiate polymorphs on the bases of their

melting point and heat of fusion (i.e. heat required to change a

substance from the solid to the liquid state).

DSC also allows to identify which form is stable and which is

metastable.


Solvates

Solvents might get trapped in the crystalline lattice, creating

solvate.

Solvates may be also referred to as pseudopolymorphs.

In general it is undesirable to use solvates for pharmaceuticals

because the presence of retained organic solvents would be

considered as unnecessary impurity in the product.


Solvates, where the incorporated solvent is water, are called

hydrates.

Anhydrous compounds are those that doesn’t include water in

their structure.

In hydrates, the entrapment is often in an exact molar ratio with

the crystallizing material, for example a monohydrate will have

one molecule of water for each molecule of the material. It is

possible to have different levels of hydrates; some drugs can exist

as mono, di and trihydrate (1, 2 and 3 molecules of water to each

molecule of drug).

Solvates - hydrates


Hydrates have very different properties from the anhydrous

form, in the same way as different polymorphs have different

properties from each other.

The most usual situation is for the anhydrous to have a faster

dissolution rate than the hydrate.

As the solvated and nonsolvated exhibit differences in

dissolution rates, they may exhibit differences in bioavailability,

particularly in the case of poorly soluble drugs.

Solvates - properties

Solid state properties Solvates - Example

Ampicillin solubility in water:

Anhydrate form sparingly soluble

>Trihydrate form slightly soluble

Higher solubility of the anhydrate

form in the GI fluids compared to

the trihydrate form.

Higher concentration of

dissolved drug available for

absorption

Higher bioavailailability


Amorphous state

Amorphous solids have atoms or molecules randomly

placed as in a liquid.

Amorphous solid have different properties from the

crystalline form of the same material.


Amorphous state - Tg

Amorphous solids do not have a melting point.

Amorphous forms have a characteristic temperature (called

glass transition temperature or Tg) at which there is a major

change in properties.

If the sample is stored below the Tg the amorphous form will

be brittle and described as the glassy state.

If the sample is stored above the Tg it becomes rubbery.


Amorphous state - properties

The solubility of amorphous solids is higher than that of

crystalline solids (Advantage). Thus, whether a drug is

amorphous or crystalline affects its therapeutic activity.

Amorphous form are often not thermodynamically stable.

Therefore: upon storage, amorphous solids tend to revert to

the most stable crystalline form (problem).

Solid state properties Amorphous state - properties

Amorphous forms tend to absorb more easily water than

crystalline forms.

Solid state properties Preparation of amorphous solids

Large molecular weight species (e,g. polymers) often cannot

form crystals, therefore they tend to be present as amorphous

forms.

For low molecular weight materials, the amorphous form may

be produced if during the preparation, the solidification process

is fast. In this case the molecules might not have time to align

into crystals.

Alternatively, an amorphous form may formed by grinding (i.e.

milling) of solid crystals.


Amorphous solid- Preformulation

Amorphous solid can be used to improve the bioavailability of

poorly soluble drugs.

However, often, their instability (intended as tendency to

convert into crystal forms over time) limits their application.

In the Preformulation stage, identification of an amorphous

can be achieved with XRPD and DSC.


Solids

Habit (external structure)

Internal structure

Amorphous Crystalline


Crystal habit

As said before, the internal structure (or lattice) is the molecular

arrangement within crystalline solids.

The crystal habit is the description of the outer appearance of

a crystalline solid, in other word the crystal habit is the external

shape of the crystal.

There are six basic crystals shape:


Crystal habit

A single internal structure (i.e. lattice) for a compound can

have several different habits.

Changes in the internal structure usually gives different habits.


Different external shape

(crystal habits) does not

necessary indicate

different internal

structure (polymorphs)


Crystal habit

Cristal habit can influence properties of the drug, such as

powder flow, compressibility, specific surface area, dissolution

rate, etc.

During preformulation, crystal habits are usually described by

their shapes under a microscope (platy, equant or massive,

needle or acicular etc.)

Hygroscopicity

Many drug substances, especially water soluble salts forms, have the tendency to absorb atmospheric moisture.

Deliquescent material absorb sufficient water to dissolve completely (MgCl2).

Also, many drugs and pharmaceutical excipients absorb moisture to form hydrates.

Hygroscopicity

Changes in the moisture level of a hygroscopic material greatly affects its physiochemical properties (including its chemical stability).

The extent of this absorption phenomena is highly dependent on the atmospheric humidity.

Other factors affecting the extent of absorption are :

temperature,

surface area of the solid

extent of exposure

Hygroscopicity In Preformulation, hygroscopicity of a compound is usually tested by:

1. Placing samples of the bulk drug in open containers with a thin powder

bed to assure maximum atmospheric exposure.

2. These samples are then exposed to a range of controlled relative

humidity environments.

3. Moisture uptake is then monitored at different time points.

4. Percentage-of-weight gain(due to moisture uptake) data are plotted

against time.

These preliminary results can give suggestions on formulation, handling,

packaging and storage requirements for the drug (e.g. hygroscopic drug

might require packaging with a dessicant).

Density, flow and compression properties

Manufacturing processes frequently involve the movement,

blending, manipulation and compression of powders.

Density, flow and compression properties of the drug powder

will have an important influence on the manufacturing

process.

It is important to investigate such properties early (i.e. in the

preformulation stage), so to guide later on the formulation

scientist in the formulation development.

Such properties of powders will be studied in depth in following

Chapters

Accelerated stability studies (stress testing): The drug substance

(API) is subjected to harsh conditions, in order to have a quick idea

about its stability and excipient compatibility. These test studies include both solution and solid-state experiments.

Drug/ excipient compatibility studies: A number of excipients of

each category (diluent, binder, lubricant) are combined with the

API and exposed to harsh storage conditions.

Storage conditions:

Elevated temperature: 40, 50 and 60 °C with dry conditions.

Humidity: 75% RH.

Light: 400 and 900 foot candle for 4 and 2 weeks, respectively.

Stability & compatibility studies

Upon completion of the preformulation evaluation of a new

drug candidate, a comprehensive report is generally prepared

highlighting pharmaceutical characteristics and problems

associated with this molecule.

This report should include recommendations for developing

possible formulations of the drug.

Formulation recommendation

Pharmaceutical preformulation · 2018-12-31 · Preformulation The objective of the Preformulation...

Documents

Transcript of Pharmaceutical preformulation · 2018-12-31 · Preformulation The objective of the Preformulation...