This document discusses various techniques for enhancing the bioavailability of drug formulations, including cocrystallization, copolymerization, and PEGylation. Cocrystallization involves forming a crystalline complex between an active pharmaceutical ingredient and a co-crystal former, which can improve solubility and bioavailability. Copolymerization uses block copolymer micelles to encapsulate hydrophobic drugs and improve their solubility. PEGylation attaches polyethylene glycol chains to proteins and peptides to increase their circulating half-life and protect them from degradation. The document examines each technique in more detail and concludes that proper selection of a bioavailability enhancement method is key to developing an effective drug formulation.

1. Bioavailability Enhancement
of Formulations:
Cocrystal, Copolymer and
PEGylation
Kushal Saha
MPH/10008/19
Pharmaceutics

2. Contents
 Introduction
 Significance of Bioavailability
 Causes of low bioavailability
 Biopharmaceutical Classification System
 Co-Crystalisation
 Co-polymerization
 PEGylation

3. Introduction:
Bioavailability: Bioavailability is defined as rate and extent of absorption of unchanged drug from it’s dosage
form and become available at the site of action. Bioavailability of a drug from it’s dosage form depends upon
3 major factors:
 Pharmaceutical factors
 Patient related factors
 Route of administration
Absolute Bioavailability: If the systemic availability of a drug administered orally is determined by doing its
comparison with I.V. administration, it is known as absolute bioavailability.
AUC extravascular DOSE intravenous
F= X
AUC intravenous DOSE extravascular
Relative Bioavailability: If the systemic availability of a drug administered orally is determined by doing
its comparison with that of an oral standard of the same drug, it is known as a relative bioavailability.
AUC extravascular1 DOSE extravascular2
F(rel) = X
AUC extravascular2 DOSE extravascular1
So, now we will know the significance of bioavailability, so that we can understand the need
of the enhancement procedures of it.

4. Significance of Bioavailability
1. Drugs having low therapeutic index, e.g. cardiac glycosides, quinidine, phenytoin etc. and narrow margin of
safety e.g. antiarrythmics, antidiabetics, adrenal steroids, theophylline.
2. Drugs whose peak levels are required for the effect of drugs, e.g. phenytoin, phenobarbitone, primidone,
sodium valporate, anti- hypertensives, antidiabetics and antibiotics.
3. Drugs that are absorbed by an active transport, e.g. amino acid analogues, purine analogues etc. In addition,
any new formulation has to be tested for its bioavailability profile.
4. Drugs which are disintegrated in the alimentary canal and liver, e.g. chlorpromazine etc. or those which
undergo first pass metabolism.
5. Formulations that give sustained release of drug, formulations with smaller disintegration time than
dissolution rate and drugs used as replacement therapy also warrant bioavailability testing.
6. Drugs with steep dose response relationship i.e. drugs obeying zero order kinetics / mixed order
elimination kinetics ( e.g. warfarin , phenytoin, digoxin, aspirin at high doses, phenylbutazone).
CAUSES OF LOW BIOAVAILABILITY
• First pass metabolism
• Poorly water soluble, slowly
absorbing oral drugs Insufficient
time for absorption in GIT Poor
dissolution (highly ionized and
polar)
• Age, stress, disorders, surgery etc.
• Chemical reactions
• Metabolism by luminal micro flora

5. Biopharmaceutical Classification
System
The Biopharmaceutical Classification System (BCS) has been a prognostic tool for assessing the potential
effects of formulation on the human drug oral bioavailability. The therapeutic efficacy of solid dosage forms is
dependent upon bioavailability of the drug, which in turn is determined by its solubility and dissolution rate
at the site of absorption.
Four classes of
biopharmaceutical
classification system
with examples
 Now we will discuss some novel methods by which bioavailability of formulations
can be improved.
In 2000, the FDA promulgated the BCS system as a science-based approach to allow waiver of in vivo
bioavailability and bioequivalence testing of immediate-release solid oral dosage forms for Class 1 high
solubility, high permeability drugs when such drug products also exhibited rapid dissolution.

6. Co-Crystalisation
Co-crystals consists of API and a stoichiometric amount of a pharmaceutically acceptable co-crystal former
Pharmaceutical Co-crystals are nonionic supramolecular complexes and can be used to address physical
property issues such as solubility, stability, & bioavailability in pharmaceutical development without changing
the chemical composition of the API. Cocrystal is a crystalline entity formed by two different or more
molecular entities where the intermolecular interactions are weak forces like hydrogen bonding and π- π
stacking Co-crystallization alters the molecular interactions and composition of pharmaceutical materials and
is considered a better alternative to optimize drug properties. Co-crystals offer a different pathway, where
any API, regardless of acidic, basic, or ionizable groups, could potentially be co-crystallized.
This aspect also helps complement existing methods by reintroducing molecules that had limited
pharmaceutical profiles based on their nonionizable functional groups. Co-crystallization actually helps
enhancing the solubility of formulations.
The thermodynamic solubility of crystal forms is directly related to their dissolution rate, which critically
impacts the pharmacokinetic profile of the orally delivered APIs. This direct proportional relationship of rate
of dissolution to exposure of a poorly soluble API has been well established and therefore remains engrained
in the form selection process.
For APIs with solubility-limited bioavailability, a challenging task in the product development is to improve
their solubility while maintaining stability and other performance characteristics. Thus, choosing the best
crystalline form of an API is an essential step in the drug development process. Over the past few years,
cocrystals have remarkably impacted the field of pharmaceutical
research.

7. Co-crystallization is broadening the intrinsic values of
APIs primarily due to their ability to alter the bulk
physical properties without tampering with the
pharmacological behavior of compounds at molecular
level.
Therefore, cocrystals may provide new opportunities for
addressing issues related to solid-state physicochemical
properties such as stability or longer shelf life, solubility
and dissolution, and thus possibly the bioactivity
Various possible solid state forms for an API
Salt formation is an acid-base reaction involving the
transfer of protons from acidic to basic species, and
generally the salts are expected to form if the ΔpKa [ΔpKa
= pKa (base) – pKa (acid)] is greater than 2 or 3.
Thus, the interactions are charge assisted, restricting the salt formation only to those APIs having ionizable
groups. Moreover, crystalline salts with the appropriate properties might be impossible to find, especially for
acidic compounds with fewer pharmaceutically acceptable counter ions than those of basic compounds.
In contrast cocrystals contain at least one un-ionized component and can be used for both ionizable and non-
ionizale APIs. In addition, a cocrystal consisting of three or even more components is possible, such as a
cocrystal containing the salt of an API and a guest compound.
Merits

8. Design, Evaluation and
Application

9. Co-polymerization
Block copolymer micelles are generally formed by the self-assembly of either amphiphilic or oppositely
charged copolymers in aqueous medium. The hydrophilic and hydrophobic blocks form the corona and the
core of the micelles, respectively.
The presence of a nonionic water-soluble shell as well as the scale (10–100 nm) of polymeric micelles are
expected to restrict their uptake by the mononuclear phagocyte system and allow for passive targeting of
cancerous or inflamed tissues through the enhanced permeation and retention effect.
The capacity of block copolymer micelles to increase the solubility of hydrophobic molecules stems from
their unique structural composition, which is characterized by a hydrophobic core sterically stabilized by a
hydrophilic corona. The former serves as a reservoir in which the drug molecules can be incorporated by
means of chemical, physical or electrostatic interactions, depending on their physicochemical properties.
Beyond solubilizing hydrophobic drugs, block copolymer micelles can also target their payload to specific
tissues through either passive or active means.
Prolonged in vivo circulation times and adequate retention of the drug within the carrier are prerequisites to
successful drug targeting. Long circulation times ensue from the steric hindrance awarded by the presence of
a hydrophilic shell and the small scale of polymeric micelles. Indeed, micelles are sufficiently large to avoid
renal excretion (N50 kDa), yet small enough (b200 nm) to bypass filtration by inter-endothelial cell slits in the
spleen. Apart from enhancing the water-solubility of many hydrophobic drugs, polymeric micelles can modify
the biodistribution of drugs through either passive or active targeting strategies.

10. PEGylation
The term ‘PEGylation’ can be defined as the covalent attachment of polyethylene glycol (PEG) chain to
bioactive substances.
Protein and peptide drugs hold great promise as therapeutic agents. However, many are degraded by
proteolytic enzymes, can be rapidly cleared by the kidneys, generate neutralizing antibodies and have a short
circulating half-life. Pegylation, the process by which polyethylene glycol chains are attached to protein and
peptide drugs, can overcome these and other shortcomings By increasing the molecular mass of proteins and
peptides and shielding them from proteolytic enzymes, PEGylation improves pharmacokinetics.
The FDA has approved PEG to use as a vehicle or base in foods, cosmetics and pharmaceuticals, including
injectable, topical, rectal and nasal formulations. PEG shows very little toxicity and lacks immunogenicity.
• To improve drug solubility.
• To reduce dosage frequency, without diminished
efficacy with potentially reduced toxicity.
• To extend circulating life.
• To Increase drug stability.
• To enhance protection from proteolytic
degradation.
• Opportunities for new delivery formats and
dosing regimens.
• To Extend patent life of previously approved
drugs.
The purpose of PEGylation

11. Three different strategies of PEGylation Technology:
1. Chemical PEGylation Technology
2. Enzymatic PEGylation Technology
3. Genetic PEGylation Technology
Contd…

12. Conclusion
Solubility is the most important physical characteristic of a drug for its oral bioavailability, formulation,
development of different dosage form of different drugs, therapeutic efficacy of the drug and for quantitative
analysis. Proper selection of solubility enhancement method is the key to ensure the goals of a good
formulation.
Here, I have discussed only three novel techniques to enhance bioavailability, but apart from these, there are
several methods to improve the bioavailability of formulations. They are,
1. Traditional techniques, like co-solvency, hydrotropy, micronization, alteration of pH of solvent, use of
surfactants, complexation etc.
2. Newer and novel techniques, like nanoparticle technology, nanocrystal technology, high pressure
homogenization, sonocrystallisation etc.
3. Vesicular approaches, like liposomes, niosomes, pharmacosomes etc.
An appropriate method can be selected by considering the properties of drug to be formulated and the
properties of desired dosage form. Other possible methods are yet to be explored in the field of
pharmaceutical particle technology that can be used to formulate various drugs with poor aqueous solubility.

13. 1. Benet, Leslie Z. “The Role of BCS (Biopharmaceutics Classification System) and BDDCS (Biopharmaceutics
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doi:10.1016/j.ajps.2014.05.005.
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Soluble Drugs.” Journal of Analytical & Pharmaceutical Research, vol. 7, no. 1, 2018,
doi:10.15406/japlr.2018.07.00198.
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References

14. Thank You
For further queries,
please contact-
kushal10saha@gmail.com