SPECIAL THANKS TO Ismail mortada (university of DUBAI)
This article will continue what I started regarding physio-chemical factors affecting the drug & it’s absorption, in past article we spoke about some factors like the chemical form of the drugs & the partition coeffecient inaddition to the ionization constant & the effect of the PH, in this article we’ll continue talking about the crystal formation of the drug
CRYSTAL FORM OF THE DRUG
Many drugs can exist in more then one crystalline form & such crystalline forms are referred to as polymorphs & the phenomena is reffered to as polymorphism , Some examples of drugs which exhibit polymorphism includes the following
Chloramphenicol palmitate (used for thyroid problems), Cortisone acetate, methyl prednisol, tetracyclines, sulphonamides, barbiturates & griseofulvin
Various polymorphic forms of a drug have identical chemical structure but different crystalline structures & they show different physical properties such as Melting points, Solubility & Dissolution rates, As you know having the same chemical structure doesn’t mean to have the same orientation in 3D shapes in nature,These properties will have a direct effect on the absorption rate & hence the bioavailibility of a drug, the arrangement of the internal packed molecules of the drug determines if it is polymorphic or not, means it have a special arrangement or not + if there is any solvent molecules (water for example as in hydration or any other organic solvent as in solvation) if there is any of those molecules or not
At a given temperature only one crystalline form of the different polymorphs will show a highly stable organized & strongly bonded crystalls form, this is referred as to the stable form, while the other crystal forms exhibit poorly organized & weakly bonded crystal forms which will be reffered to the Metastable forms
So the metastable form of the polymorphic drug as it shows a poorly organized crystal form, which means weakly bonded also, will have a low melting point & thus a higher solubility & high dissolution rate (as less energy is required to break its bonds), While the stable form exhibits high melting point & low solubility & dissolution rate (as being highly organized & strong bonded so more energy is needed to break its bonds), Accordingly, in order to have high dissolution rates & hence high absorption rates, that’s why the metastable form of polymorphic drug might be always required & recommended over the stable form from absorption point of view, so metastable form is almost the preffered choice normally unless we need a sustain release of the drug which I’ll discuss later in this article
Some examples of the influence of crystal form on the bioavailibility is as the following
EXAMPLE 1
Chloramphenicol palmitate exists in polymorphs having a stable & metastable forms, the metastable form of the drug if formulated as a suspension was always found to have higher solubility, dissolution rate & absorption compared to the stable form
EXAMPLE 2
Methylprednisolone exist as a metastable & stable form & if the drug is formulated as a suspension for subcutaneous injection containing the 2 crystalline forms, then that means a sustained release of the drug can be obtained where the metastable form (being highly soluble compared to the stable form) can provide a rapid initial dose (loading dose), while the stable form (being slowly dissolved) will provide the prolonged or sustained action dose called the maintenance dose
please note the following plot graph but reject the names of the compounds and concentrate on my explanation please
In the past plotted graph (while forgetting the names of the compounds) consider basically the following lines with blue, yellow & pink colours
It’s obvious that the blue colour dissolves more slowly then the pink one for example because the concentration of any point of the blue dissolved drug is lower (at the same time) compared to the pink one
The blue line can be considered the plot of a stable crystal form of a drug & the pink one can be considered the plot of a high dissolved metastable form of the same drug
AMORPHISM
In addition to different polymorphic forms, A drug may exist in an amorphous form, which is a non-crystalline or poorly crystallized form
Since amorphous form is usually more soluble & rapidly dissolving (but having shorter duration of action) than the corresponding crystalline form so it will exhibit a higher dissolution rate & absorption rate also, some examples showing the effecr of the amorphous form of a drug on bioavailibility is as the following
EXAMPLE 1
The amorphous form of novobiocin (antibiotic) found when taken orally as a suspension, found to possess high absorption while crystalline form of the same drug was found to be poorly absorbed * therapeutically ineffective
EXAMPLE 2
Similarly the amorphous form of chloramphenicol stearate is found to be highly bioavailable, while the crystalline form is therapeutically ineffective
EXAMPLE 3
A mixture of amorphous & crystalline forms of insulin taken subcutaneously or by IM route provide an initial rapid action dose due to the fast disssolving amorphous form followed by a prolonged action because of the slowly dissolving crystalline form
In general the mixtures or usage of the crystalline stable, metastable or un-crystallized form (the amorphous form) is depending on the preparation & the target of the drug, also depending on the ease of manufacturing & separating different forms from each other, there must be a special ratio also when we come to speak about mixtures of different forms, this ratio depends on a lot of other factors also mentioned normally in pharmaceutics studies
SOLVATION & ASOLVATION
During the process of crystallization, the drug crystals may incorporate (include) one or more molecules of the solvent used into their internal structures & the result is referred to as solvates
The effect of solvate & asolvate (hydration is used if the solvent was water & solvation if it was any other organic solvent) form (asolvate means drug molecule crystalls containing no solvent molecules trapped between them) on the dissolution rate or permeation rate is great hence effecting directly the total bioavailibility of the drug which will varie (the bioavailibility) greatly between different drug forms & crystals forms depending on the type of the solvent trapped
When the solvent is water, the anhydrated form (the asolvate) generally shows high dissolution rate than their corresponding hydrates (solvates) & hence shows higher bioavailibility, This is because the anhydrous forms of the drug reacts more extensively with water compared to the already hydrated form which is considered to have a level of water saturation already, Some examples of the effect of hydrates & unhydrates on the dissolution & hence bioavailibility of the drug is shown as the following
EXAMPLE 1
The anhydrous forms of the following drugs exhibits higher dissolution rates compared to their corresponding hydrated form such as caffeine, theophylline & glutethimide
EXAMPLE 2
The anhydrous form of ampicillin, when taken orally in a hard gelatin capsule formulation was found to possess higher dissolution rates & higher absorption rates than ampicillin trihydrate, which is obviously the hydrated form of ampicillin
On the other hand, when organic solvates are used (other than water), the drug will exhibit higher bioavailibility when it is in the solvate form rather than the other asolvate form, This maybe due to the fact that organic solvates has higher lipophilicity (partition coeffecient) due to their non-aqueous or lipophilic enviroment in general surrounding the drug molecule & hence will increase the rate of permeation of the drug via the GIT leading to general enhanced absorption & bioavailibility rate, Some examples showing the effect of organic solvates on the bioavailibility are shown as the following
EXAMPLE 1
The ethanol & acetone solvates of hydrocortisone & prednisolone show higher absorption rates than the non-solvated forms
EXAMPLE 2
The chloroform solvates of griseofulvin (anti-fungal) is better absorbed than the same drug asolvate
So in general we see that crystal formation & the trap of any solvent molecule between the drug crystalls will highly & directly effect the whole process of absorption & bioavailibility in different manners & this can be used to study the effects of drugs & to formulate special sustain release forms or to increase the bioavailibility of some other drugs
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