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Development of biopharmacy

Expression „biopharmaceutics” was composed

By Gerhard Levy and it was written down by
John G. Wagner in a publication from 1961 Gerhard Levy
for the first time.

Knowledge accumulated from the field of biopharmacy

reached a level which was able to be functionable as a
separate discipline. Wagner later declared the birth of the
biopharmacy as: „a body of knowledge which needed a
name”

Wagner, J.G.: Biopharmaceutics: Absorption aspects, J. Pharm. Sci., 50, p 359-387.

1961.
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 What is biopharmacy?

Biopharmacy is a pharmaceutical discipline which could be used

by the modern drug discovery, quality control and
pharmaceutical attendance.

Biopharmacy investigates the connection between

the medicine and the living organism.
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Development of biopharmacy
Investigates the characteristics and behaviour of the API
and the medicine in the human body.

Biopharmaceutics:

-models the processes accompanying the interactions of the medicine

and the human body

-reveals the main physical, chemical and pharmacological

characteristics of the medicines

- examines the pharmacodynamic and/or toxicologic reactions of the

human body and the development of the effect

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LADME system

liberation
invasion
absorption

distribution
disposition
metabolism
elimination
excretion

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 Liberation

Liberation means the relase of the API from the dosage form.

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 Arthur Amos Noyes Willis Rodney Whitney
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 Coated tablet with
Capsule containing a tablet immediate effect. Inner
Intestinosolvent coated with three layers matrix releases the API
granules slowly

Osmotic tablet with Matrix tablet with Tablet composed by

zero order kinetics controlled release compressed micropellets

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Dissolution testers (1,2,3,4)

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Dissolution run

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 Place of sampling
• It should be in the middle of the medium level and
upper level of the paddle/basket.
• It should be at least 10 mm from the container.
• Sampled and analysed medium should be
– injected back, or
– substituted with clean medium, or
– taken into account the eliminated amount.

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Transdermal drug dissolution

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Evaluation of drug release

1.) model-independent

2.) model-dependent evaluation

Evaluation of dissolution tests

Pairwise comparison of dissolution data by appropriate

staticstical methods
 Model-independent methods

fit factors (f1 , f2 )

Method compares the reference dissolution data to the test preparation .

f1 difference factor f2 similarity factor

∑ (R − T ) i i ⎧
⎪⎡ 1 n ⎤
−0 , 5
⎫
⎪
f1 = i =1
n
×100 f 2 = 50 lg⎨⎢1 + ∑ (Ri − Ti )⎥ *100⎬
∑R i
⎩⎣ n i =1
⎪ ⎦ ⎪
⎭
i =1

n no. of samples,
Ri dissolution % at ‘i’ time of the reference preparation,
Ti dissolution % at ‘i’ time of the test preparation
Evaluation of drug release tests

1. ) With theoretically valid background

2. ) Without theoretical background, based on

experiences
Model-dependent methods

Zero order dissolution kinetics

m m = kt

m = kt
m
c=
V
t
m API amount at ‘t’ time
t time
c API % at ‘t’ time
k rate constant
Model-dependent methods

First order kinetics

ln m

dm
= km
dt
m = mo e − kt
(ln m − ln mo ) = kt

t
Model-dependent methods

General model:
Weibull model

m / m∞ = 1 − exp{ −[( t − to ) / τ ]} β
t −t o β
−[ ]
m / m∞ = 1 − e τ

m dissolved API % at ‘t’ time

m∞ dissolved API % at t=∞ time
t time
t0 lag time
τ time of 63,2% API dissolution
β shape factor
 Absorption

The API enters the systemic circulation

• There is no absorption at iv. medicines

• There are several factors affecting the
absorption at per os administration

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Transcellular transports summary

Passive Facilitated Active

Characteristics
diffusion diffusion transport

needs carrier
no yes yes
molecule

selective no yes yes

can be saturated no yes yes
can be inhibited no yes yes
against
concentration no no yes
gradient
needs energy
no no yes
(ATP)

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Passisve diffusion

The most frequent type of transport of APIs.

Apolar, non-ionised APIs can cross the

membrane according to the concentration
gradient.

This type of transport lasts until the equilibrium in

concentration, it does not need energy.

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Ionisation

Degree of ionisation of molecules is calculated by the Henderson-Hasselbalch

equation. Using this formula the ratio of ionised and non-ionised amount of
molecules can be determined which highly depends on the pH of environment.

In case of weak bases: C non − ionised

pH − pK a = lg
C ionised

In case of weak acids: C ionised

pH − pK a = lg
C non − ionised

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Ionisation

100%
bases
Degree of ionisation

50% pKa=3,5 pKa=7,0 pKa=10,5

acids

3,5 7,0 10,5 14 pH

 pH values
GI tract

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 Distribution
API(s) enter the tissues from the systemic circulation

• APIs are usually distributed unequally

between different tissues, they can
accumulate in different organs

– ie. Penicillin cannot enter through the blood-brain

barrier
– Compartment models
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 Metabolism
Biotransformation of the API

• Medicines are xenobiotics (foreign material) for

the human body
• Decreases or terminates the effect of the drug
• On the contrary it can accelerate the effect

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 Excretion
Terminal disposal of the API or its decayed forms

• Kidney
• Bile
• Lungs
• Any humour

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 Biopharmacy based Pharm. Technology

Aim is to produce a preparation which is able to

release the API at the proper…

- - site of action,

- - amount (concentration),

- release rate

In order to suit these rerquirements, it is important to get acquanted

with the biopharmaceutical characteristics of the medicine.

Biopharmaceutical basics

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2017. október 31. 32
 Gordon L. Amidon,
Amidon et al. published the importance of
Biopharmaceutical Clasification System (BCS) in 1995,
which is an important characteristic of the preparation’s
bioavailability.

According to their suggestion APIs can be categorized into

four groups regarding the gastrointestinal absorption by their
solubility and permeability characters.
APIs can be categorized into four groups according to their solubility and
permeability:
Class I Class II
High solubility Low solubilitiy
Permeability High permeability High permeability

Human
intestinal Class III Class IV
absorption
High solubility Low solubility
Low permeability Low permeability

Solubility

Volume of water required to dissolve the highest dose

streght across the physilogical pH range (1.2 ; 4.5; 6.8 )
Literature shows that there is an increasing number of poorly soluble
compounds in the drug discovery pipeline – including 70 per cent BCS
Class II compounds – although only about 30 per cent are BCS Class II in
the existing top 200 market

New chemical entities Top 200 marketed drugs in USA

Unclassified
10%
IV. 20% I. 1,5% I. 31%
IV. 6%

III. 5%

III. 23%

II. 70% II. 30%

 Class I Cass II
Sources of
pharmaceutical micronisation,
technology to increase nanoparticles,
solubilisation, solid
the bioavailability of dispersion, salt forming, self
drug delivery systems emulsifying systems,
complexes, buffers,
accourding to the BCS surfactants, liquid-filled

Permeability
capsules

Class III Class IV

solubilisation,
submicroscopic particles,
lipophilic capsules, GI nanoparticles, co-solvents,
motility enhancers salt forming, solid
mucoadhesion, dispersion, amorphous
absorption-enhancer form, self emulsifying
efflux inhibitors systems, complexes,
buffers, liquid-filled
capsules with absorption-
enhancer
Solubility
 Thank you for your
attention!

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