Module 3 Method development – selection of test conditions.pdf

USP’s Perspective on Drug Product

USP s Perspective on Drug Product

Performance Test

Method Development

•

Dissolution testing is a sequence of complex

processes

processes

– Sample preparation in dissolution apparatus – Sample collection

Sample processing (e g ; filtration) – Sample processing (e.g.; filtration) – Sample transfer and storage

Analysis to determine the concentration of drug – Analysis to determine the concentration of drug

substance released

– Computation of % dissolved with reference to label claim

claim

•

Many experimental factors or attributes can affect the

final test results

Method Development

•

Quality Dissolution Methods:

l t – relevant – predictive

Method Development

• The dissolution procedure requires – An apparatusAn apparatus

– A dissolution medium

– Operating conditions (rpm, temperature, sampling schedule)

• The method needs to be discriminating yet sufficiently

rugged and reproducible for day-to-day operation and capable of being transferred between laboratories

being transferred between laboratories

• One product may require more than one dissolution test – e.g.; for combination products

– Still all requirements to be fulfilled for all of the API’s

Discriminating Dissolution Test

• Procedure should be appropriately discriminating, capable of distinguishing significant changes in a composition or

distinguishing significant changes in a composition or

manufacturing process that might be expected to affect in vivo performance

• Procedure may show differences between batches when no significant difference is observed in vivo

Batch-to-Batch Quality and Intra-Batch Homogeneity

• The dissolution test should appropriately reflect relevant changes in the drug product manufacture

in the drug product manufacture

• The results from multiple batches should represent typical

i bilit i iti d f t i t

variability in composition and manufacturing parameters may assist in this evaluation

• May be valuable to intentionally vary manufacturing parameters, such as lubrication, blend time, compression force, or drying

parameters, to further characterize the discriminatory power of the procedure

procedure

Advance Knowledge: Know Your Product

•

API

– Physical properties • particle size

• structure (amorphous, crystalline) – Physico-chemical propertiesy p p

• solubility • pKa

• Intrinsic dissolution • Intrinsic dissolution – Chemical properties

• salt form • stability

– Biopharmaceutical properties • permeabilityp y

Advance Knowledge: Know Your Product

•

Formulation

t – type

– excipients – site of action

– release characteristics – manufacturing process – marketing considerationsmarketing considerations

•

Particle Size

– significant effect on dissolution • surface area

– crystalline vs. amorphous – Micronisation

Development of dissolution methods

`

Experimental test conditions should consider

•

Characteristics of the dosage form

– Route of administration – Administered dose

– Time of administration – Time of administration

•

Chemistry of API

– Solubility

St bilit

– Stability

•

Physiology

– Medium

• Composition • pH value

– Volume

– Temperature

Physico-Chemical Characterization of API

`

Solubility in various aqueous media

H d

d

t

l bilit

•

pH dependent solubility

– Buffer solution with different pH values, e.g. pH 1 to pH 8

•

Influence of salt composition

– different composition of buffer solutions at the same pH value

•

Use of solubilizing agents

– To improve wettabilityTo improve wettability – To improve solubility

•

Effect of various surfactants (if applicable)

Diff t f t t t ( i i i i ti i )

– Different surfactant types (e.g. non-ionic, anionic, cationic) – Different concentrations of the same surfactant

•

Simulation of food effect (if applicable)

API - Physical Properties

Structure -

dimenhydrinate

diphenhydramine

API - Physico-chemical Properties

Solubility

0 1 2 3 4 5 6 7 8

0,0 ,

pH

pH-solubility profile of Dimenhydrinate mean values (n = 3) SD pH-solubility profile of Dimenhydrinate, mean values (n = 3), SD

API - Physico-chemical Properties

• pKa / solubility: verapamil pKa 8.6

solubility

dissolution

solubility

dissolution

Krämer, J.; Blume, H.: Biopharmaceutical Aspects of Multiparticulates. In:

API – Physical Properties

‹

Highly soluble – highest dose is soluble in

g y

g

250 mL of medium in the pH range from 1

to 7.5, or pH 6.8

API - Chemical Properties

Stability

Time [h] Recovery [%]

6 99

12 98

18 97

24 93

Stability of the synthetic sample solution SDS

Time [h] Recovery [%]

Time [h]

6 99

12 99

18 99

18 99

API - Biopharmaceutical Properties - Permeability

API – Biopharmaceutical Properties in Comparison

Permeability

API – Physical Properties

‹

Highly permeable – absorption in humans

g y p

p

is higher than 90% of the dose

administered

API - Biopharmaceutical Properties

Biopharmaceutical Classification (BCS)

p

(

)

‹ Class I – high solubility / high permeability

‹ Class II – low solubility / high permeability

‹ Class III – high solubility / low permeability

‹ Class III high solubility / low permeability

Selection of the Apparatus

•

API solubility and stability characteristics

– High solubility

L l bilit

– Low solubility

•

Dosage form

– Solid oral dosage forms

– Semisolid dosage forms, etc

•

Physiology of site of in-vivo dissolution

– Gastro-intestinal tract – Gastro intestinal tract – Skin, etc

•

Release mechanism

I di t l

– Immediate release – Modified release, etc

•

Regulatory expectations

Selection of Dissolution Apparatus

•

The choice of apparatus is based on

D f d f l ti d i

– Dosage form and formulation design

•

For solid oral dosage forms

– Apparatus 1 and Apparatus 2 are used most frequentlypp pp q y

•

Some changes can be made to the apparatus when

the need is clearly documented by supporting data

a basket mesh size other than the typical – a basket mesh size other than the typical

40-mesh basket (e.g.; 10, 20, 80 mesh) – Use of a sinker

A t 5 (P ddl di k) – Apparatus 5 (Paddle over disk)

•

Agitation can be adjusted as needed

Selection of Dissolution Medium

•

Based on physical and chemical data for

Drug substance – Drug substance

• Solubility of drug substance – Sink conditions maintained

• Stability of drug substance at different pH conditions – Drug product

• Immediate release, delayed release, extended release, , y , , transdermal patch, etc.

• Theoretical drug release mechanism, if known

• For Modified Release Dosage Forms also to proveFor Modified Release Dosage Forms also to prove – Robustness of dosage form

– For development of ER dosage forms more than one medium required (topographical characterization)

Selection of Dissolution Medium

`

Aqueous buffer solutions pH 1.2 – pH 6.8

` Modified-release formulations up to pH 7.5

`

Reflect the pH conditions at the dissolution site

`

Addition of :

` bile salts (sodium cholate, sodium taurocholate)

` surfactants (sodium lauryl sulfate, polysorbates)

` ( i ti )

` enzymes (pepsin, pancreatin)

`

Sink-conditions are desirable

`

Use of aqueous-organic solvent mixtures are allowed in specific

cases (investigation of the dosage form robustness)

Example: Buffer vs. Purified Water

Appropriate Medium

Phenprocoumon API 8 0

1 0 0

p pKa 5.12

Solubility in Water

4 0 6 0

% dissolved

Product Dissolution @ pH 6.8

700 800 900

0 1 0 2 0 3 0 4 0 5 0 6 0 0

2 0

1 0 0

mins 300 400 500 600 L ö sl ic h k eit [ m g /l] 6 0 8 0

4 5 6 7 8

0 100 200

0 1 0 2 0 3 0 4 0 5 0 6 0 0 2 0 4 0 mins % dissolved 25

Product Dissolution @pH 5.2

Selection of the Volume of Dissolution Medium

`

Basket/ Paddle Apparatus

` special cases: 2 or 4 liter

` low dose: 150 ml - 250 ml (not compendial)

`

Reciprocating Cylinder Apparatus

` Use of up to 6 vessels for testing

`

Flow-through Cell Apparatus

` for implants: 1 0 ml/min– 2 ml/min

` for implants: 1.0 ml/min 2 ml/min

Selection of Agitation Rate and Temperature

`

Basket Apparatus: 100 rpm

`

Paddle Apparatus: 50 rpm or 75 rpm

`

Paddle Apparatus: 50 rpm or 75 rpm

` extended release formulations: 100 rpm

`

Reciprocating Cylinder Apparatus

`

5 dips/min – 35 dips/min

`

Temperature

` Orally administered drugs: 37°C

` Orally administered drugs: 37 C

Sampling Time Point

`

Immediate-release formulations

` Development: profiles to characterize the dissolution pattern (e g 10 15 20 30 45 and 60 min)

(e.g. 10, 15, 20, 30, 45 and 60 min)

` Quality Control: single time point, e.g.15 or 30 min

`

Modified release formulations

– Acidic stage: 1 h or 2 h

– Buffer stage: similar to IR formulationsBuffer stage: similar to IR formulations

` Extended release formulations

– One early time point: 1 or 2 hours Intermediate time point: 4 or 5 hours – Intermediate time point: 4 or 5 hours

– Final time point e.g. 8, 12 or 24 hours

`

“Infinity” Time Point

Sampling Time Point

Single Time Point

Additional Sampling for Method Development

• Infinity Time Points

The paddle or basket speed is increased at the end of the run – The paddle or basket speed is increased at the end of the run

for a sustained period (typically 15 to 60 minutes), after which time an additional sample is taken

no requirement for 100% dissolution in the profile • no requirement for 100% dissolution in the profile

– Provides data that may supplement content uniformity data

– May provide useful information about formulation characteristics during initial development

– Not required for routine testing

Case Study – Felodipine Extended Release Tablets

Place each Tablet in a specially made quadrangular basket of

stainless steel wire gauze, soldered in one of its upper, narrow sides

to the end of a steel rod (see Figure 1). Place the tablet cover in the

horizontal diagonal of the basket Put the rod assembly up through horizontal diagonal of the basket. Put the rod assembly up through the cover of the dissolution vessel, and fix it by means of two teflon nuts, 3.2 cm from the center of the vessel, or by any other

appropriate means. Adjust the lower edge of the bottom of the

basket to approximately 1 cm above the top of the paddle blade (see

Oral suspensions for systemic use

` Paddle method, aqueous medium

` Representative sample: standardized procedure based on shaking or mixing

` Sample weight/volume to reflect typical dose

` Sample introduction and agitation rate based on viscosity and p g y composition of suspension matrix

– Low viscosity suspensions: Dose delivery to the bottom of the vessel by volumetric pipette; low agitation rate: 25 rpm.

– High viscosity suspensions: Dose determination by weight with quantitative sample transfer; higher agitation rate: 50 or 75 rpm

` Sample introduction - accurate, precise, and reproducible

Orally Disintegrating Tablets (ODT)

` Orally Disintegrating Tablets (ODT) create an in-situ suspension by rapidly disintegrating, typically within one minute or less p y g g, yp y

` Taste masking is an essential feature of ODT’s and can be rate determining mechanism for dissolution/release

` Follow the principles of oral dosage forms or suspensions: paddle

` Follow the principles of oral dosage forms or suspensions: paddle method at 50 rpm; single point specification

` If taste masking (using polymer coating) is a key aspect of the

Chewable Tablets

` Generally same procedure as regular tablets

` Same test conditions as for conventional tablets of the same active

` Same test conditions as for conventional tablets of the same active pharmaceutical ingredient (where applicable)

` Non-disintegrating nature of the dosage form may require different test conditions (e g increased agitation rate) and specifications test conditions (e.g., increased agitation rate) and specifications (e.g., increased test duration)

` Reciprocating cylinder with addition of glass beads provide intensive agitation

Suppositories

` Hydrophilic suppositories

– basketbasket

– paddle

– flow-through cell

` Lipophilic suppositories

– modified basket method

ddl ith i d d i k

– paddle with a wired screen and sinker

– modified flow-through cell with specific dual chamber suppository cell (Ph. Eur. 2.9.3.-6.)

Liquid-Filled Capsules

`

Hydrophilic or

`

Lipophilicformulations

`

Lipophilicformulations

– may or may not include a surfactant

` Paddle method with a minimum amount of surfactant, if needed

` Difficulties to keep the formulation immersed

` Modified dual chamber flow-through cell

– Open systemOpen system

– Closed system

` Basket method

` R i ti li d

Transdermal Patches

` Method of Choice:

– Paddle over disk (USP Apparatus 5) with a watch glass-patch screenPaddle over disk (USP Apparatus 5) with a watch glass patch screen

sandwich assembly

– Rotating cylinder (USP Apparatus 6)

– Reciprocating disk (USP Apparatus 7)p g ( pp )

– Paddle over extraction cell (Ph. Eur. 2.9.4.2)

` pH of the medium ideally pH 5 – pH 6 (physiological skin condition)

` Test temperature: 32°C (skin temperature)

` Test temperature: 32 C (skin temperature)

` 100 rpm

Semisolid Topical Dosage Forms

` Non-compendial dissolution apparatus

– Vertical diffusion cell (Franz cell) with synthetic membraneVertical diffusion cell (Franz cell) with synthetic membrane

– Semisolid Holding Cell System

– Modified USP Apparatus 4 cell systems

` With or without using synthetic membranes

` With or without using synthetic membranes

` Receptor medium may need to contain alcohol and/or surfactant

` De-aeration critical to avoid bubble formation at membrane interface

` Test temperature: 32°C (skin temperature)

Typical Drug Release Profiles of Semisolid Dosage Form

In vitro Drug Release

Cortaid (1% Hydrocortisone) Cream

300 200 250 R el eased pe r c m 2 ) Run 1 Run 2 50 100 150 A m ount R (m ic ro gr a

m Run 2

Run 3

0 50

5 7 9 11 13 15 17 19 21

S R t f Ti ( i )

Enhancer Cell

`

PTFE holder

`

Various surface areas and adjustable cell volume

`

Various surface areas and adjustable cell volume

`

Used with conventional dissolution apparatus

`

100 or 200ml vessel with mini-

paddle

p

`

Drug products

` Ointments and creams

Challenges

`

Selection of the testing conditions

` Composition of the drug release medium

` Composition of the drug release medium

` Bubble formation after sampling

Injectable Depot Dosage Forms

` Modified flow-through cell

– low flow ratelow flow rate

– Tests are often run over a long time period (e.g., several weeks) Take measures against evaporation, microbial contamination

` Osmolarity, pH and buffer capacity of the medium should reflect the

` Osmolarity, pH and buffer capacity of the medium should reflect the site of application (plasma or muscle)

` Challenge:

Appropriate duration of the test and sampling times to adequately – Appropriate duration of the test and sampling times to adequately

characterize the release profile

– Stability of the API over the entire testing time

– Evaporation of the mediumEvaporation of the medium

` Possibility of accelerated test conditions is attractive (elevated temperatures and pH values - faster drug release)

` Verification of validity of the accelerated test conditions

Real Time Drug Release Testing Conditions

`

USP App. 4 operated as “closed” system

` 12-mm diameter flow-through cells

` Cells packed with 1 mm glass beads

(microspheres mixed with glass beads to avoid aggregation)

T

`

Temperature

`

Medium

`

Medium

` 250 mL of Phosphate buffer saline (PBS) pH 7.4

`

Filter

` 1.0 µm fiberglass

`

Flow Rate

` 4 35 mL/min

Accelerated in vitro Release Method

`

Accelerated in vitro release method by studying effects due to:

` Increased temperature

` Changes in dissolution medium

– use of hydroalcoholic solutions – change in pH value

– addition of surfactant

` Flow rate

– varied between 4 and 35 mL/min

In vitro Release Profile of a Microsphere Injectable

100

Real-time drug release profile

70 80 90 100 R el eas e 40 50 60 70 ive P ercen t R 10 20 30 Cu mu la ti 0

0 10 20 30 40 50

Time (Days)

Accelerated Release Test

45 deg C; n=3

0 0.1 0.2 0.3

F

0 50 100 150 200

Tim e (Hours)

Correlation of real time and accelerated release profiles

y = 0.1439x + 0.5091

2 3 4 e ra te d Ti m e

R2 = 0.9887

0 1 2 Ac c e le

20 25 30 35 40 45