2017. 05. 11.

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The significance of

biopharmaceutical formulation in the

development of generic products

Istvan Antal, Ph.D.

Department of Pharmaceutics

Semmelweis University, Budapest

Review objectives

Biopharmaceutical aspects of

• API characteristics

• Composition characteristics

• Manufacturing technology

(composition/manufacturing technology )

and properties to ensure drug release

Biopharmaceutical approach…

Drug substance

+

formulation factors(excipients, technological process)

Tolerable and

effective

Biological response

Process Physiological condition Changes

Liberation motility

acid and enzyme secretion

pH, buffer capacity

secretion of digestive fluids

pH, hydrodynamics

surfactant (bile) , lumen content viscosity

volume used for administration

absorption rate (dilution), food components

Absorption acid secretion, pH

motility

absorption area

blood flow

drug release rate (concentration gradient)

food-interaction

preabsorptive metabolism

Distribution body water content

body weight

fat percent

amount of plasma proteins

plasma proteins

competitive drugs for binding

Metabolism Liver mass,

Liver blood flow

Liver cell condition

Enzyme activity

Enzyme induction/inhibition

first-pass effect

interaction with drugs and/or food

Excretion kidney blood flow

glomerular filtration rate

urine pH

agents influencing active tubular secretion

Effects of physiological conditions

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Nelson 1957

Dissolution, absorption, elimination

Nelson, E. (1957), Solution rate of theophylline salts and effects from oral

administration. J. Pharm. Sci., 46: 607–614.

A B Cka ke

Significance of bioavailability (Gerhard Levy, 1972)

BIOPHARMACEUTICAL CLASSIFICATION SYSTEM (BCS)

Classification by the solubility

and intestinal permeability of drug molecules (Amidon: 1995)

BCSSolubility of active ingredient

High Low

Permeability of

active ingredient

High Class I Class II

Low Class III Class IV

highly variable:

• pH

• motility (transit)

• food interactions

Factors influencing drug absorption

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- Dosage schedule

- Dosage time

- interval

- Before , with, after meals

- To avoid interaction (time periods)

- Function of the dosage forms

(e.g. intact, subdivided if possible)

Patient compliance „Development pharmaceutics”

Original, generic, „MR generic”

Selection of the dosage form (appearance)

Dose/strength selection

Development of laboratory manufacturing technology

Development of pilot plant laboratory manufacturing technology

(Validation) > bioavailability/bioequivalence

Industrial scale technology

Validation (BA/BE)

"Biopharmaceutics encompasses the study of the relation

between the nature and intensity of the biological

effect observed in animals and man, including the

following factors:

I) The nature and form of the drug (ester, salt, complex,

etc.)

2) The physical state, particle size, surface area

3) The presence or absence of excipients, adjuvants

4) The type of dosage form in which the drug is

administered

5) The pharmaceutical technological process used to

prepare the formulation and dosage form"

API and Dosage Forms Related Factors affecting a

product’s bioequivalence

• I. Active ingredient– 1. Crystal structure

– 2. Polymorphism

– 3. Solvate, hydrate

– 4. Particle size

– 5. Surface Area

– 6. Aqueous solubility

– 7. Salt

– 8. Complexation

– 9. Prodrug,

– 10.Solid Dispersion

– 11.Ionization degree, pKa

– 12.Partition coefficient

• II. Dosage form– 1. Type of dosage form

(aqueous solution,

suspension, soft

gelatine capsule, tablet,

coated tablet, enteric

coated tablet

– 2. Disintegration

– 3. Dissolution

– 4. Production variables

– 5. Excipients

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Routes of drug administration related to

biopharmaceutics, pharmacokinetics, pharmacodynamicsParenteral route with injection

Route Bioavailability Advantage Disadvantage

Intravenous

bolus (IV)

Complete (100%)

systemic drug

absorption.

Distribution and onset

are instantaneous.

Drug is given for

immediate effect.

Increased chance foradverse reaction.

Possible anaphylaxis.

Intravenous

infusion (IV inf)

100% of dose into

systemic circulation

Rate of drug input

controlled by infusion

rate.

Plasma drug level Is more

precisely controlled.

May inject large fluid

volumes.

Drugs with poor lipid

solubility and/or irritating.

Requires skill in insertion of infusion set.

Tissue damage at site of injection (infiltration,

necrosis, or sterilé abscess).

Intra muscular

injection (IM)

Rapid from aqueous

solution.

Slow absorption from

nonaqueous (oil)

Solutions.

Easier to inject than

intravenous injection.

Larger volumes may be

used compared to

subcutaneous Solutions.

Irritating drugs may be very painful.

Different rates of absorption depending on muscle

group injected and blood flow.

Subcutaneous

injection (SC)

Prompt from aqueous

solution.

Slow absorption from

repository formulations.

Generally used for insulin Rate of drug absorption depends on blood flow and

injection volume.

Enteral route

Route Bioavailability Advantage Disadvantage

Oral (PO) Absorption may vary.

GeneraIly, slower

absorption rate

compared to IV bolus or

IM injection.

Safest and easiest

route of drug

administration.

May use immediate-

release and modified-

release drug products.

Somé drugs may have erratic absorption, be

unstable in the gastointestina 1 tract, or be

metabolized by liver prior to systemic

absorption.

Intraoral

Buccal (BL)

or sublingual

(SL)

Rapid absorption from

lipid-soluble drugs.

No "first-pass" Some drugs may be swallowed.

Not for drugs with high doses.

Rectal Absorption may vary

from suppository

excipients.

More reliable absorption

from enema (solution).

No "first-pass"

Useful when patient

cannot swallow

Absorption may be erratic.

Patient discomfort.

Suppository may migrate to different position.

Other routes

Route Bioavailability Advantage Disadvantage

Transdermal Slow absorption, rate

may va ry.

Increased absorption

with occlusive dressing.

Transdermal delivery system

(patch) is easy to use.

Used for lipid-soluble drugs

with low dose and low MW.

May be irritant by patch or drug.

Permeability of skin variable with

condition, anatomic site, age, and

gender.

Type of cream or ointment base

affects drug release and absorption.

Inhalation

Rapid absorption.

Total dose absorbed is

variable.

May be used both for local

or systemic effects.

Particle size ofdrug determines

deposition

May stimulate cough reflex.

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Process for Innovator and Generic Product

Innovator Product___ Generic Medicinal Product

1. Chemistry 1. Chemistry

2. Manufacturing 2. Manufacturing

3. Controls 3. Controls

4. Labeling 4. Labeling

5. Testing 5.Testing

6. Animal Studies

7. Clinical Studies 6.Bioequivalence

8. Bioavailability

Generic Medicinal Product(Guideline on the Investigation of BE, EMEA 20.01.2010)

• ….is a product which has the

• same qualitative and quantitative composition in active substances and

• same pharmaceutical form as the reference medicinal product and whose

• bioequivalence with reference medicinal product has been demonstrated with

appropriate bioavailability studies.

• Different salts,

esters, ethers,

isomers, mixtures of isomers,

complexes as derivatives of an active substance are considered to be the

same active substance, (unless they differ significantly in properties with regard to safety and/or efficacy.)

• Same active ingredient(s)

Salt, base, anhydrous, hydrated, inclusion complexes

• Same route of administration

!• Same dosage form

! ….

• Same strength

! ….

Demands for generics:

+ Same quality• dissolution profile• impurity profile• stability profiles

+ Different appearance (e.g. same size, same shape, but different color)

Concepts of the development

• proportional composition (API ratio)

• direct compression technology if possible

• solid state stability

• patent connsiderations

• manufacturing/processing problems

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21

Dosage form characteristics are influenced by

• the chemical characteristics of the active ingredient,

• its physical state,

• the extent of stability,

• the applied excipients

• and the operation parameters of the applied technology.

Pharmaceutical technology aspectsEssential data for the formulation

• Compound identity

• Structure

• Formula and molecular weight

• Therapeutic indications

– Probable human doses

– Desired dosage form(s)

– Bioavailability model(s)

– Competitive products

• Potential hazards

Solubility pKa

Partition coefficient (logP)pH-dependent logDChemical stability profile Crystal Properties and Polymorphism Particle size, shape and surface area

Evaluation of possible dosage form

Salt-formation is one of the most used approaches

to increase drug aqueous solubility.

Hydrochloride is the most common salt form for

medications.

In addition, acetate, bromide, chloride, citrate, maleate,

phosphate and sulfate are also used to form various

drug salt forms.

The formation of salts will not alter the pKa of the parent

drug compound.

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Large solubility differences can be is observed between disordered and ordered state of the same compound. The solubility ratio (Samorphous/Scrystalline) of the amorphous and crystalline forms at a certain temperature is determined by the difference in their energy level:

ecrystallin

amorphous

S

SRTG ln−=∆

The difference in free energy can be estimated from entropy, enthalpy and heat capacity values as was shown for indomethacin. Polymorphs of the same compound exhibit small solubility differences (less than 10 times) due to small differences in their free energy. The theoretical solubility difference between the amorphous and crystalline form could be up to several hundred times.

Polymorphic and amorphous materials

Structuralpolymorphism

Crystalline form

PolymorphsMolecular adductssuch as solvates or

hydrates

Nonstoichometricadducts

Stoichometricadducts

Amorphous form

• Particle morphology

– Optical microscopy (normal/polarization)

– Electron microscopy

• Particle size distribution

– Sieve analysis

– Laser diffraction

• Structure (crystalline/polimorphic, amorphous)

• Processabbility (melting point, flowability)

• Higroscopicity

– Water adsorption (gravimetry/Karl Fischer titration)

– Automatic dynamic water sorption analysis

Solid state characterization

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Strcutural analysis

• Crystalline state

– microscopy

– X-ray powder diffractogram

(XPRD)

– DSC/TG

Differential Scanning calorimetry

termogravimetry

26,0

26,2

26,4

26,6

26,8

27,0

27,2

27,4

27,6

27,8

28,0

-2,00

-1,75

-1,50

-1,25

-1,00

-0,75

-0,50

-0,25

0,00

0,25

0,50

30 55 80 105 130 155 180 205 230 255 280

DSC TG

Solubility and melting point

Melting point (⁰C)

So

lub

ilit

y(m

g/m

l)

•melting point (hot stage microscopy);

•infrared spectroscopy;

•XRPD;

•thermal analytical techniques (DSC, differential thermal

analysis DTA, TGA, etc.);

•solid-state Raman spectroscopy;

•crystalline index of refraction

• phase solubility analysis;

• solution-pH profile determination;

• solution calorimetry

• comparative intrinsic dissolution rates

Methods for evaluating physicochemical properties of solid

materials Processability and preformulation

Melting point is related to drug solubility somehow.

In general, the lower the melting point of a compound, the larger

its solubility will be. Vapor pressure could affect drug stability and

content uniformity for those volatile active ingredients.

Hygroscopicity can reduce certain processing capability.

These are less important properties in preformulation compared to

solubility and polymorphism.

However, detailed information on the characteristics certainly is

helpful to minimize the potential problems related to

preformulation and formulation process.

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Processability and preformulation

Bulk characterization– Crystallinity and polymorphism

– Hygroscopicity

– Fine particle characterisation

– Bulk density

– Powder flow properties

Morphology is related to physical characteristics

important in processability, such as

blending

granulation

compression

filling

Qualitative composition is known

But

- API characteristics?

- quality and quantity of excipients?

- manufacturing technology

- patent situation/infringement?

(better to use not the claimed excipient)

Development of generic dosage forms

Development of „MR generic” dosage form

in vitro dissolution profile?

In vitro – in vivo correlation?

API characteristics (e.g. particle size)?

excipients?

manufacturing technology?

In vitro in vivo correlation (IVIVC)

Dissolution Plasma level

in vitroIn vivo response

IVIVR

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Development Process ActivitiesLab scale development

Pharmaceutical Technology activities Testing Required

PREFORMULATION

- API characterization

salt, solid state, particle size

- Excipients functionality selection

- Drug-Excipient compatibility study

(4-8°C, 50°C & 50°+75% RH)

- Solubility, Particle Size Distribution (PSD),

IR, DSC, assay, impurities, etc.

- Visual Inspection

- HPLC Semi-quantitative impurities

evaluation

PROTOTYPE

FORMULA

FEASIBILITY

- Preliminary formula evaluation

o Polymer type and level evaluation: e.g.

Hydroxypropylmethyelcelluose (HPMC) to be used to

modulate drug release.

o Filler type and level evaluation

o Other excipients (Lubricant, glidant, etc.)

o Tablet weight and shape trials

Preliminary manufacturing process evaluation

o Solid phase transition?

o Pretreatment (precoating of solid surface)

o Granulation or Direct Compression

o Final blend characterization

o Compression process

Preliminary stability study

(HDPE bottles)

o Preliminary formulations to be placed under stability:

At least 1-3 months for a first assessment at:

� 25°C + 60% RH

� 30°C + 65% RH

� 45°C + 75% RH

- Dissolution profile testing (preliminary

(dissolution method development is

required)

- Blend Uniformity Analysis (BUA),

LOD%/KF, blend flowability evaluation

- Dissolution profile, Assay.

- Tablets Content Uniformity (CU)

- Tablets characteristics: hardness, friability,

etc.

- Dissolution profile, Assay, Impurities

Solid state stability during the processing

Avinash G. Thombre: DDT Volume 10, Number 17 • September 2005

Excipient

The intended function of an excipient is to act as

- the carrier (vehicle or basis) or as a

- component of the carrier of the active substance(s) and,

in so doing, to contribute to product attributes

� such as stability,

� biopharmaceutical profile,

� appearance and

� patient acceptability and

� to the ease with which the product can be manufactured.

Usually, more than one excipient is used in the formulation of a medicinal

product.

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DRUG

EXCIPIENT

PATIENT CONVENIENCE

flavoring/sweetening agents,

tonicity agents, buffers

MANUFACTURABILITY

Carrier constituents

liquid vehicle, ointment/supposittory base,

diluent/filler, propellant

Processing aids : binder, glidant, lubricant,

compression aid, suspending/emulsifying agent, etc.

STABILITY

Chemical stabilizers

antioxidant, adsorbent,

moisture binder,

complexing agent, pH modifier,

colorant

Antimicrobiological agents

preservatives

Physical stabilisers

dispersing agent, viscosity-

enhancer, surfactant

MODIFIED RELEASE

& ABSORPTION

disintegrant

wetting agent

matrix former

coating material

biodegradable polymer

penetration enhancer

bioadhesive agent

EFFICACY SAFETY

QUALITY

IDENTITY&

APPEARANCE

coloring agents

Role and functions of drug excipientsH. Kalász, I. Antal: Drug Excipients, Current Medicinal Chemistry, 13: 2535-2563 (2006)

Compatibility

Role and functions of drug excipientsH. Kalász, I. Antal: Drug Excipients, Current Medicinal Chemistry, 13: 2535-2563 (2006)

e.g. microspectroscopy or AFM

Modern analytical techniques serving the reverse engineering

The formulation work needs

• biopharmaceutical approach,

• patient centric concepts,

• optimized processing technology

• optimized drug release according to physical

structure, composition, and manufacturing

technology,

Summary