Biopharmaceutical Considerations in Drug Product Design

Introduction

The biological availability of a drug is a result of many processes. Factors such as low solubility, slow dissolution or release rate, poor permeability, gastrointestinal degradation, and rapid biotransformation may all contribute to poor availability.
Experience has shown that these factors can be studied individually and that many possible problems can be anticipated before the drug reaches the clinic.
The relationship between the physicochemical properties of a drug in a dosage form and the biological response (including bioavailability) observed following its administration is the subject of an area of drug research known as biopharmaceutics.
The proper design and formulation of a dosage form requires consideration of the physical, chemical, and biologic characteristics of all of the drug substances and pharmaceutical ingredients to be used in fabricating the product.

Biopharmaceutical Considerations in Drug Product Design

Drugs are not generally given as a pure chemical but formulated into a finished dosage form (drug product).
A formulated drug product usually includes the active drug substance and selected ingredients. A primary concern in biopharmaceutics is the bioavailability of drugs.
Bioavailability refers to the measurement of the rate and extent of drug that reaches the systemic circulation.
The aim of biopharmaceutics is to adjust the delivery of drug from the drug product in such a manner as to provide optimal therapeutic activity and safety for the patient.
Each route of drug application presents special biopharmaceutical considerations in drug product design. Example: 

• the design of a vaginal tablet formulation for the treatment of a fungal infection must consider ingredients compatible with vaginal anatomy and physiology.
• an eye medication may require special biopharmaceutical considerations including appropriate pH, isotonicity, sterility, local irritation to the cornea, draining by tears, and concern for systemic absorption.

The rate of drug release from the product and the rate of drug absorption are important in determining the distribution, onset, intensity and duration of the drug action.
Biopharmaceutical considerations often determine the ultimate dose and dosage form of a drug product.

Requirements of a proper design and formulation of dosage form

Consideration of drug substances:

• Physical, chemical and biological characteristics
• compatible with one another  – stable, efficacious, attractive, easy to administer and safe
• manufactured under appropriate measures of quality control and packaged in containers to make product stable
• labeled to promote correct use and stored under conditions to maximize shell life

The need for dosage forms

• To protect the drug substance from the destructive influences of atmospheric oxygen or humidity (coated tablets).
• To protect the drug substance from the destructive influence of gastric acid after oral administration (enteric-coated).
• To conceal the bitter, salty or offensive taste or odor of a drug substance (capsules, flavored syrups).
• To provide liquid preparations of substances that are either insoluble or unstable in the desired vehicle (suspension). 
• To provide clear liquid dosage forms of substances (syrups, solutions)
• To provide rate-controlled drug action (controlled-release tablets).
• To provide optimal drug action from topical administration sites (ointments, creams, transdermal patches).
• To provide for insertion of a drug into one of the body’s orifices (suppositories).
• To provide placement of drugs directly in the bloodstream or body tissues (injections).
• To provide for optimal drug action through inhalation therapy (inhalants, inhalation aerosols).

General considerations in dosage form design

• Determine desired product type – framework for product development.

• Develop and examine initial formulations of the product:
  • desired features: drug release profile  bioavailability clinical effectiveness
    • pilot plant studies and production scale-up.

• Master formula
  • formulation that best meets the goals of the product

Factors to consider before formulation of a medicinal agent in one or more dosage forms:

• therapeutic matters (nature of the illness)
• manner  it is treated (locally or through systemic action)
• age and anticipated condition of the patient.

Design and formulation of drug products

• Require a thorough understanding of the biopharmaceutical principles of drug delivery.
• Biopharmaceutics studies the in vitro impact of physicochemical properties of drugs and drug products on delivery to the body under normal or pathologic conditions. 
• Bioavailability is the assessment of the rate and extent at which the active drug becomes available at the site of action. 

Biopharmaceutical Considerations

Biopharmaceutics enables the rational design of drug products through the understanding of:

• Physical and chemical properties of the drug substance
• Therate of administration including the anatomic and physiologic nature of the site of application
• Desiredpharmacodynamic effects (immediate or prolonged activity)
• Toxicologicproperties of the drug
• Safetyand compatibility of excipients
• Effectof excipients and dosage form on drug delivery

By choosing the route of administration carefully, and properly designing the drug product, the bioavailability of the active drug can be varied from:

• Rapid and complete absorption through
• Slowsustained rate of absorption, to
• No absorption at a site (depending on the therapeutic objective of the formulation.)

Physico-chemical nature of the drug

The physico-chemical nature of the drug and excipient would affect: 

• Dissolution kinetic of drug product, 
• Stability of product
• Risk to manufacturing personnel in drug production. 

Rate and extent of drug availability in the systemic circulation depends on a number of physicochemical and physiologic factors. 
These physicochemical factors include the: 

• ionization constant
• partition coefficient, 
• solubility and dissolution rate,
• crystal form, 
• surface area of drug substance and the dosage form. 

The physiologic factors include the gastro-intestinal environment and its effect on:

• drug solubility,
• drug permeability through gastro-intestinal membrane and 
• the pH profile of GIT, 
• presence of bile salts and other physiologic surfactants, 
• effect of food and disease conditions of the subjects. 

Contribution of solubility
The contribution of solubility to the potential of a candidate’s suitability as medicinal substance is very significant.
Drugs that were subjects of intense scientific and regulatory scrutiny in the 1970s and 1980s were those with poor aqueous solubility, generally in the range of 20 – 100 μg/mL.
Nowadays, drug substances of solubility as low as 1 μg/mL are quite common. 
Considerable attention has been paid to how to control drug substance solubility and permeability.
Drug molecules have now been classified into different categories based on their physicochemical properties. 

Effect of physicochemical properties on oral absorption

Physicochemical properties have provided models/tools for predicting oral absorption during dosage form design and development.
Most important physicochemical property-based models include:

• pH-Partition theory,
• AbsorptionPotential (AP),
• MassBalance,
• CompartmentalAbsorption &Transit (CAT) Models

The Lipinski’s “Rule of Five”

The Lipinski’s “Rule of Five” provides experimental and computational approaches to the estimation of solubility and permeability in drug discovery and early developmental stage based on physicochemical properties of new drug molecules. 
This rule of 5 states that poor absorptions or permeations are more likely when:

1. there are more than 5 hydrogen bond donors (expressed as the sum of OHs and NHs)
2. there are more than 10 H-bond acceptors (expressed as the sum of Ns and Os)
3. the Molecular Weight is over 500
4. the log partition coefficient is over 5

Compound classes that are substrates for biological transporters are exceptions to the rule.

Rate-limiting factors in oral drug absorption

Physicochemical considerations

1. State of dispersion and formulation factors
2. solubility
3. dissolution rate
4. release from dispersed system
5. chemical stability

2. Transport properties of the molecules

1. lipophilic/hydrophilic balance- often determines permeability
2. pka – determines ratio of charged to uncharged species at a given pH
3. molecular size and shape- determines diffusivity

Biological considerations

A. Stomach

1. pH
2. emptying rate
3. surface tension
4. enzyme

B. Intestinal tract

1. pH
2. transit time and reserve length
3. lumenal contents
4. microclimate pH
5. lumenal and brushborder metabolism
6. nature of biomembrane
7. mucosal cell metabolism
8. basolateral membrane restriction to transport
9. lymphatic absorption
10. p-glycoprotein (p-gp), multi drug resistant transporters (MDR), solute transporter (SLT)

Salt Selection 

Salt selection is a critical part of the drug development process because selection of an appropriate salt can significantly reduce time to market.
Salts are used to alter the physical or chemical properties of a drug substance. If the correct salt is selected, subsequent development will be facilitated.
In addition, salts that exhibit advantageous properties are usually patentable as new chemical compounds.
The change in crystal structure that can be accomplished by salt formation can lead to greatly improved properties.
In many cases, substances containing free acid or base groups have poor aqueous solubility.
Conversion of these groups to salt forms often improves solubility, thus providing greater bioavailability.
It is sometimes the case that a salt provides increased chemical or physical stability compared to the parent drug substance.
Salts can also provide a means of purification and/or a way to improve the handling properties of a drug substance.
A good salt should possess the following desirable characteristics:

• Acceptable organoleptic properties
• Easy to synthesize
• Good flow and compaction properties
• Minimal hydration and in addition:

• Non-toxic
• Reproducible particle size and size distribution
• Stable
• Suitable aqueous solubility and intrinsic dissolution characteristics

• Suitable bulk density
• Suitable and sharp melting point.
• Non-irritating to veins
• Non-hygroscopic

Excipients Selection

Depends on intended dosage form:

• • Tablets & capsules:
    • Lubricants, binders, disintegrants, diluents
  • Parenteral: Tonicity agents, antioxidants, buffers, preservatives
  • Rational stability studies  
  • Wide range of products with multinational market authorization
  • Evidence of bioequivalence
    • To generate meaningful results
    • Avoid stresses that cannot be extrapolated to normal conditions of handling 

Crystal properties

• Polymorphism
  • Monotropic 
  • Enantiotropic 
• Pseudopolymorphism 

Other factors affecting solubility

• Temperature
• Common ion effect
• Solubilization 
• Crystal purity

• Crystal properties and solubility
• Polymorphism and solubility

Read also:

Biopharmaceutics Classification System (BCS) and Biowaivers