Effect of Excipients on Dissolution: Case Studies with Bio ... · Effect of Excipients on...

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Effect of Excipients on Dissolution: Case Studies with Bio-relevant/

Hydro-alcoholic Media

Sandip B. Tiwari, Ph.D.Technical Director: South Asia

Colorcon Asia Pvt. Ltd., Goa, India

DISSO-INDIA 2013, May 03-04, 2013


Outline

Dissolution test: basics

Tests before bio-study

— What controls the release profiles

• Formulation excipients or test conditions

— Variability levels of the formulation: effects of excipients/ technology

— Fed and fasted effects

Effect of hydro-alcoholic media: effect of formulation excipients


Oral Drug Delivery

Heart

Liver(Metabolism?)

Drug Mouth Stomach

Drug Release from Dosage Forms

Drug Dissolution

Drug Absorption

Membrane Transport

SmallIntestine

LargeIntestine

Rectum

Mucosal lining

Site of Action ?

Reasons for poor bioavailability:No dissolution at absorption siteDegradation / non absorbable complex / metabolism / Low permeability


Dissolution Test

A measure of the proportion of drug dissolving in a stated time under standardized conditions in-vitro.

The Pharmacopoeia stresses that in the majority of cases no attempt has been made to correlate dissolution results with in-vivo data.

In a few cases, the in-vitro dissolution data correlates with in-vivoperformance.

Quality control:- Process control- Batch-to-batch quality


Factors Affecting Dissolution of an API

Intrinsic dissolution rate (substance related)— Chemistry, polymorphic nature, crystalline or not, etc

Volume of liquid to dissolve in!— Differences between GIT and USP

Composition of the media— Difficult to replicate the GIT due to its variability

Agitation rate— Differences between USP methods and GIT

Time allowed to be dissolved / removed (absorbed)— Sink condition (differences between USP and GIT)

Immediate environment (formulation type/ excipients) Other factors: temperature, viscosity, surface area etc


USP Dissolution ApparatusUSP apparatus Suitable for Agitation method Standards

1 Basket Solids, beads, capsules, floaters, MR

Rotating stirrer • 40 mesh basket• 100 rpm• 900 ml at 37°C

2 Paddle Solids, suspension, MR, Patches

Rotating stirrer • Inert material• 900 ml at 37°C• 50 rpm• Sinkers

3 BioDis Non-disintegrating tablets and Beads, MR

Dipping rate • Mesh screen at top and bottom

• 200-250 ml

4 Flow-through cell Solids, powders, beads, implants

Fluid movement Variations in Size, flow rate, filters

5 Paddle over disc Patches Rotating stirrer • 900 ml• 32° C

6 Cylinder Patches Rotating stirrer •900 ml• 32° C

7 Reciprocating holder Patches, solids Reciprocation • Sample holder• 50-200 ml• 32° C


Antral contraction waves

Does the Dissolution Tester Simulate This?


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Paddle 50rpmBasket 50 rpmPaddle 100rpmBasket 100rpmPaddle 75rpmBasket 75rpm

Diltiazem HCl ER Tablet Release inBuffer Media at 370 C


Biorelevant Dissolution Media

Fasted state Stomach:

— FaSSGF: simulates reduced surface tension in the stomach Small intestine:

— FaSSIF to simulate basal bile secretion Colon: SCOF (pH 5.8 acetate buffer)

Fed State Stomach:

— Ensure® Plus to simulate gastric conditions after a standard breakfast

Small intestine: — FeSSIF to simulate postprandial bile secretion, increased buffer

capacity and osmolality after food intake

Based on J. Dressman’s recommendation


HCl (pH 1.2-2.0) 0.01-0.05 N

Pepsin 1.0 mg/ml

Na Taurocholate 80 µM

Sodium chloride 2.0 g

Distilled Water qs 1000 ml

In Vitro Simulation of the Gastric Contents: Preprandial (FaSSGF)

Based on Vertzoni et al. J.Pharm Pharmacol. (2005)


NaH2PO4 1.977 gSodium taurocholate 3 mMLecithin 0.75 mMNaCl 3.093 gNaOH qs pH 6.5Distilled Water qs 500 ml

pH 6.5Osmolality 270 + 10 mOsmBuffer Capacity 10 + 2 mEq/L/pH unit

Simulation of Fasted State in the Small Intestine: FaSSIF


Simulation of Fed State in the Small Intestine: FeSSIF

Acetic acid 8.65 gSodium taurocholate 15 mMLecithin 3.75 mMGlycerolmonooleate 5 mMNaCl 11.874 gNaOH qs pH 5Distilled Water qs 1 Liter

pH 5Osmolality 635 + 10 mOsmBuffer Capacity 76 + 2 mEq/L/pH unit


Simulating GIT: USP Apparatus 3 (BioDis®)

Useful for non disintegrating tablets / beads MR dosage forms


• variable volumes: 200−250 ml per vessel

• dip rate 5–40 dpm: variable motility patterns

• mesh sizes 75-840 µm: variable hydrodynamics

• complex media: food effects

• 6 rows of vessels →variable pH values and media

• different residence times per medium → variable passage times

USP Apparatus 3 - BioDis®


Case Studies: Testing Setup

Tests 8 tablet at a time

Six sequential media for each tablet

Automatic sampler for each media at programable times

Sample Analysis using HPLC

Adjustable dip rates and screen sizes for variable

hydrodynamics

— 20, 30, 40 Mesh

— 5 to 40 dpm


Case Studies: Bio-relevant Media and Physiological Residence Times

** Halved bile salts


Verapamil 240mg ER Formulation Based on HyperStart®

Material %w/w mg/tablet

Verapamil HCl 47.8 240.0HPMC (Methocel K100LV CR) 30.0 150.0HPMC (Methocel E5)* 0.4 2.0Lactose-spray dried (Fast Flo NF) 20.9 105.0Colloidal silicon dioxide (CAB-O-SIL M-5)

0.5 2.5

Magnesium stearate NF 0.5 2.5

Total: 100.0 502.0

*Methocel E5 was used as a wet granulation binder


Verapamil 240mg ER (n=6) USP II- 50 & 100rpm

Dissolution medium –900ml of simulated gastric and intestinal fluid no enzymes (37 ± 0.5°C)

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Verapamil HCl 240 mg SR USP Low USP High


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Verapamil HCl 240mg ER USP Low USP High Isoptin SR

Verapamil 240mg ER (n=6) USP II- 100rpm

Dissolution medium –900ml of simulated gastric and intestinal fluid no enzymes (37 ± 0.5°C)

Marketed Brand


Fasting state Fed state

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Colorcon ADS-I

Calan® SR 240 mg

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Colorcon ADS-I

Calan® SR 240 mg

Verapamil 240mg ER: Apparatus 3


Colorcon Formulation Innovator Formulation

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Calan® SR 240 mg Fasted

Calan® SR 240 mg Fed0

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Colorcon ADS -1 Fasted

Colorcon ADS -1 Fed

Verapamil 240mg ER: Apparatus 3


Carbamazepine 200mg ER Formulation Based on HyperStart®

Material Supplier %w/w mg/tablet

Carbamazepine Max Pharma, DE 57.14 200.00HPMC (Methocel® K100LV CR) Colorcon Ltd, UK 30.00 105.00

MCC 90µm (Avicel® PH102) FMC, Ireland 10.95 38.32HPMC (Methocel® E3LV)* Colorcon Ltd, UK 0.16 0.56Sodium lauryl sulphate** Stepan, UK 0.50 1.75Fumed silica (Aerosil® 200) Degussa, France 1.00 3.50

Magnesium stearate Peter Greven, UK 0.25 0.87Total: 100.00 350.00

* Methocel E3LV was used as a WG binder.** Sodium lauryl sulphate (SLS), a surfactant was used within the binder solution to improve carbamazepine solubility.


Carbamazepine 200mg ER (n=6) USP I – 100 rpm

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Carbamazepine (200mg) ER Matrix

USP Lower Acceptance Criteria

USP Upper Acceptance Criteria

Dissolution medium - 900ml of purified water, 37.0 ± 0.5ºC


Fasting state

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Colorcon ADSTegretol® XR 200 mg

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Colorcon ADSTegretol® XR 200 mg

Fed state

Carbamazepine 200mg ER: USP3



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Colorcon ADS - Fasted

Colorcon ADS - Fed

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Tegretol® XR 200 mg- FastedTegretol® XR 200 mg- Fed

Carbamazepine 200mg ER: USP3


Metformin 500mg ER Formulation Based on HyperStart®

Material Supplier %w/w mg/tablet

Metformin HCl Ferico Labs 50 500

Methocel K100M CR Colorcon 30 300

Avicel PH102 FMC 19 190

Aerosil 200 Degussa 0.5 5

Magnesium stearate Peter Greven 0.5 5

Total: 100% 1000mg


Metformin 500mg ER (n=6) USP II -100 rpm

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Glucophage XR 500mg tablets

Colorcon 500mg Metformin MR tablets

Dissolution medium - 1000ml of purified water, 37.0 ± 0.5°C


Fasting state Fed state

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Glucophage® XR 500 mg

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Glucophage ® XR 500 mg

Metformin 500mg ER: Apparatus 3



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Colorcon ADS Fasted

Colorcon ADS Fed

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Glucophage® XR 500 mg Fasted

Glucophage ® XR 500 mg Fed

Metformin 500mg ER: Apparatus 3


Some Biopharmaceutic Considerations

Transit / window of absorption Elimination path / first pass metabolism issue Fed versus fasted

— API absorption / complexation— Dosage form effects

• Osmotics • Matrices• Barrier membrane MPs

Reduced toxicity related to Cmax


Potential Effects of Alcohol on ER Dosage Forms

In July 2005 the FDA issued an alert for healthcare professionals regarding an alcohol-PalladoneTM interaction.

— PalladoneTM is a once-daily opioid capsule containing pellets each of which has drug embedded in an ER matrix

— Strengths: 12 mg, 16 mg, 24 mg, 32 mg hydromorphone HCl — No food effect or pH effect

When ingested with alcohol the peak plasma concentration of hydromorphone increased to potentially lethal levels due to breakdown of the ER formulation.

The objective of this study was to investigate the influence of hydro-alcoholic solutions on the hydration, swelling and gel formation of HPMC compacts and drug release from their matrices.


Solubility of the Tested Drugs (Martindale, 1999)

Active Solubility in water

Solubility in alcohol

Felodipine Practically insoluble

“freely soluble in absolute alcohol, in

methyl alcohol”Gliclazide Practically

insoluble“slightly soluble in

alcohol”Metformin HCl

Freely soluble

“slightly soluble in alcohol”


Felodipine 5 mg HPMC ER Formulation

Material Supplier % w/w mg/tabletFelodipine Spodefell, UK 2.5 5HPMC (Methocel® K100LV CR) Colorcon Ltd, UK 37.0 74

Lactose (Fast Flo®) Foremost Farms, USA 59.5 119

Fumed silica (Aerosil® 200) Degussa, France 0.5 1Magnesium stearate Peter Greven, UK 0.5 1Total 100.0 200


Gliclazide 30 mg HPMC ER Formulation

Material Supplier % w/w mg/tabletGliclazide Synergy Enterprises,

India15.0 30

HPMC (MethocelK100LV CR)

Colorcon Ltd, UK 35.0 70

Microcrystalline cellulose 90m

FMC, Ireland 49.0 98

Fumed silica (Aerosil®200)

Degussa, France 0.5 1

Magnesium stearate Peter Greven, UK 0.5 1Total 100.0 200


Metformin HCl 500 mg HPMC ER Formulation

Material Supplier % w/w mg/tabletMetformin HCl Ferico Labs,

India50.0 500

HPMC (Methocel K100M CR) Colorcon Ltd, UK 30.0 300

Microcrystalline cellulose 90m FMC, Ireland 19.0 190Fumed silica (Aerosil® 200) Degussa, France 0.5 5

Magnesium stearate Peter Greven, UK

0.5 5

Total 100.0 1000


Dissolution Media Selection

5% v/v ethanol 40% v/v ethanol


Stomach

Duodenum

Jejunum

Ileum

Ascending colon

For How Long to Test in Hydro-Alcoholic Media?


Felodipine Release Profiles12 hours in

hydro-alcoholic media1 hour in

hydro-alcoholic media

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In pH 6.5 phosphatebuffer + 1% SLS

In 5% v/v ethanolsolution in phosphatebuffer + 1% SLSIn 40% v/v ethanolsolution in phosphatebuffer + 1% SLS

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1 hour in 5% v/v aqueousethanol solution1 hour in 40% v/vaqueous ethanol solution


Gliclazide Release Profiles12 hours in



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In 5% v/v aqueous ethanolsolutionIn 40% v/v aqueous ethanolsolution

Metformin HCl Release Profiles12 hours in



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Saturated Solubility of the Candidate Drugs in Various Media (g/L)

Felodipine Gliclazide Metformin HCl

Water 0.002 0.045 450.413

5% v/v ethanol in water 0.005 0.054 378.647

40% v/v ethanol in water 2.490 0.503 295.466pH 6.5 phosphate buffer + 1% SLS 0.811 - -

5% v/v ethanol in phosphate buffer + 1% SLS 0.721 - -

40% v/v ethanol in phosphate buffer + 1% SLS 4.374 - -


Values of f2 for Drug Release Profiles from HPMC Matrices in Various Media

Dissolution medium 5% v/v ethanol 40% v/v ethanolDuration of exposure to alcohol containing media

12 hours 1 hour 12 hours 1 hour

Felodipine formulation 71 76 63 63

Gliclazide formulation 80 65 79 55

Metformin HCl formulation 68 86 44 54


Hydro-Alcoholic Media Uptake of MethocelCompacts (n = 3)

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K100LV CR (0:100 ethanol: w ater)K100LV CR (25:75 ethanol: w ater)K100LV CR (50:50 ethanol: w ater)K4M CR (0:100 ethanol: w ater)K4M CR (25:75 ethanol: w ater)K4M CR (50:50 ethanol: w ater)K100M CR (0:100 ethanol: w ater)K100M CR (25:75 ethanol: w ater)K100M CR (50:50 ethanol: w ater)


In water and hydro-alcoholic solutions all compacts underwent swelling and gelation without any disruption to the matrix integrity.

A similar progressive weight gain by compacts in water and hydro-alcoholic media with time occurred.

The extent of swelling increased with increasing viscosity grade of HPMC from 100 to 4000 cps.

No significant difference in compact relative swelling was observed for Methocel K4M CR and K100M CR.

Hydro-Alcoholic Media Uptake of MethocelCompacts (n = 3)


Solubility of Tableting Fillers in Various Media (Handbook of Pharmaceutical Excipients, 2003)

What about other factors, i.e. differences in the solubility of matrix ingredients in various media?

The most commonly used fillers in HPMC matrices are microcrystalline cellulose (MCC), lactose, pregelatinized starch (PGS) and dibasic calcium phosphate dihydrate (DCPD).

The effect of hydro-alcoholic media exposure on tablets with different fillers will probably increase in the following order:MCC or DCPD -> PGS - > lactose (In felodipine formulation no significant effect)


Filler Solubility in water Solubility in alcohol

MCC Practically insoluble Practically insoluble in most organic solvents

Lactose 1 in 4.63 Practically insoluble in ethanol

PGS Slightly soluble to soluble

Practically insoluble in organic solvents

DCPD Practically insoluble Practically insoluble in ethanol

Solubility of Tableting Fillers in Various Media (Handbook of Pharmaceutical Excipients, 2003)


Conclusions

ER HPMC tablets of felodipine 5 mg, gliclazide 30 mg and metformin HCl 500 mg retained their hydrated structural integrity when exposed to 5% and 40% v/v ethanol solutions for up to 12 hours without any failure of the matrices resulting in dose-dumping.

Drug release profiles from these ER metformin HCl tablets were different when exposed to 0% and 40% v/v ethanol solutions for 12 hours that were explained by changes in drug solubility.

When the matrices were exposed to hydro-alcoholic media for only 1 hour the change in drug release profiles was not significant.


Summary

Formulation excipients or test conditions dictate the drug release profile.

Use of Apparatus I or II may not show differences in in-vitro behavior of

formulations vis-à-vis innovator formulations prior to bio-study

conclusion.

Use of Apparatus III with simulated bio-relevant media could be a good

tool to indicate performance of formulations in-vitro, and possibly in-vivo

Effect of hydro-alcoholic media on drug release profile is dictated by

solubility of API/ excipients and duration of exposure.

Effect of Excipients on Dissolution: Case Studies with Bio ... · Effect of Excipients on...

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