溶出度方法学验证-7
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12
Some points to remember
• The use of surfactants is not straightforward
– The API does not dissolve as such-it forms micelles
• Some surfactants dramatically lower surface tension which may not mimic the physiological situation [SLS]
Development of dissolution methods
Compound specific
1
Types of compounds
SPARINGLY SOLUBLE
pH INDEPENDENT
pH DEPENDENT
COMBINATION PRODUCTS
2
Poorly water soluble compounds
6
Fenofibrate
• No ionizable group (neutral)
– Soluห้องสมุดไป่ตู้ility----Practically insoluble in water
• Highest strength=160mg, • Water Solubility is 0.008mg/mL therefore BCS low solubility drug.
• Stability problems below pH 2.5 • Denaturing of enzymes used in two tier dissolution testing with crosslinking • Over effective due to excessive surface tension reduction
• Evaluate pH effects on dissolution
– 0.1 N HCl – pH 4.5 acetate buffer – pH 6.8 phosphate buffer
• Evaluate different surfactants [qualitative]
– Cationic
14
The new EMA guidance
• Investigations related to the drug product should ensure immediate release properties and prove similarity between the investigative products, i.e. test and reference have a similar in vitro dissolution considering physiologically relevant experimental pH conditions.
• Polysorbates (Tween™) • Sodium dodecyl sulfate (sodium lauryl sulfate) • Lauryl dimethyl amine oxide • Cetyltrimethylammonium bromide (CTAB) • Polyethoxylated alcohols • Polyoxyethylene sorbitan • Octoxynol (Triton X100™) • N, N–dimethyldodecylamine– N–oxide • Hexadecyltrimethylammonium bromide (HTAB)
– Quats will ion pair with carboxylic acids at 2 pH’s units above pKa
13
Specific problems with SLS
• Use in combination only with Sodium Phosphate for 6.8 pH not Potassium Phosphate—precipitates at room temp
5
Poorly soluble drugs using surfactants [USP]
Estradiol/norgestimate (1mg/0.09mg) Ethinyl Estradiol/Norgestrel Amiodarone HCl (Test 2) Dicumerol Levonorgestrel Glyburide [non-micronized] Metolazone Tolcapone Tamsulosin HCl 0.3% SLS in water Water with 5 ppm of Tween 80 Acetate Buffer, pH 4.0, with 1% Tween 80 Basket 100 rpm, 1000 mL 0.1 TRIS buffer pH 9.0, 0.1 N HCl with 0.1% SLS Paddle 75rpm. 900ml., 0.5% CTAB in pH 9.0 borate buffer Paddle 75rpm, 900 mL 2.0% SLS/Water, Borate Buffer, pH 6.8 with 1% SLS 0-2 hours: 0.003% polysorbate 80, pH 1.2 2-8 hours: phosphate buffer, pH 7.2
• Polyoxyl 10 lauryl ether • Brij 721™ • Bile salts (sodium deoxycholate, sodium cholate) • Polyoxyl castor oil (Cremophor™) • Nonylphenol ethoxylate (Tergitol™) • Cyclodextrins • Lecithin • Methylbenzethonium chloride (Hyamine™)
15
Combination products
16
Combination products
• There are two meanings of combination products
– One or more active ingredient – A combination drug and device [considered under special dosage forms]
• These may present a significant challenge
• For multiple actives a single dissolution test should be aimed for.
USP
• ….aqueous solutions may contain a percentage of a surfactant (e.g. SLS, polysorbate or lauryldimethylamine oxide) . The need for surfactants and the concentrations used can be justified by showing profiles at several different concentrations.
– However, respective results are not an acceptable way to establish an in vitro/in vivo correlation.
• The pH conditions to be employed are at least pH 1.2, 4.5, and 6.8. Additional investigations may be required at pH values in which the drug substance has minimum solubility. • The use of any surfactant is strictly discouraged.
Dissolution 54mg Fenofibrate tablet 75 rpm
http://www.aapspharmscitech.org/
AAPS pharm sci tech 2006;7(2) Art33
8
Poorly water soluble drugs: Surfactants
Medium Sol mcg/ml DI Water 0.8 0.72% SLS 195 1.44% SLS 446 2.16% SLS 728 2% Tween 80 134
9
Valdecoxib dissolution
2.0% SLS 1.5% SLS 1.0% SLS 0.5%SLS 0.2% SLS
Worrying because the rate of dissolution does not really change, only the amount dissolved
10
Ketoprofen dissolution profile
11
Surfactants used in dissolution for PWSDS
BCS guidance, solubility is high if more than 160/250=0.64 mg/mLis soluble across pH range 1-7.5 Solubility based on 250ml volume
Having no ionizable groups, fenofibrate solubility is not 7 influenced by changes of the pH of the dissolution medium
– Increased wetting may give much higher dissolution than would be achieved in the GIT
• Be aware of chemical effects with ionic surfactants
– Sulphonic acid salts will ion-pair with amines at most pH’s
• All such methods have moved to aqueous media using surfactants*
*But now alcoholic medium is used to prove absence of dose dumping3
Development steps for PWSDs
• Old methods, including Pharmacopeial methods used organic solvents
– Carbamazepine
– Danazol [IPA/0.1N HCl:4/10] – Chlorthalidone
• These created extreme artifacts and had no biological significance
– Anionic
– Non-ionic
Evaluate different surfactants [quantitative]
4
Official Statements
FDA
• A dissolution medium containing surfactant can better simulate the environment of the gastrointestinal tract than a medium containing organic solvents or other nonphysiological substances, making the dissolution test conditions more useful in evaluating drug quality.
Some points to remember
• The use of surfactants is not straightforward
– The API does not dissolve as such-it forms micelles
• Some surfactants dramatically lower surface tension which may not mimic the physiological situation [SLS]
Development of dissolution methods
Compound specific
1
Types of compounds
SPARINGLY SOLUBLE
pH INDEPENDENT
pH DEPENDENT
COMBINATION PRODUCTS
2
Poorly water soluble compounds
6
Fenofibrate
• No ionizable group (neutral)
– Soluห้องสมุดไป่ตู้ility----Practically insoluble in water
• Highest strength=160mg, • Water Solubility is 0.008mg/mL therefore BCS low solubility drug.
• Stability problems below pH 2.5 • Denaturing of enzymes used in two tier dissolution testing with crosslinking • Over effective due to excessive surface tension reduction
• Evaluate pH effects on dissolution
– 0.1 N HCl – pH 4.5 acetate buffer – pH 6.8 phosphate buffer
• Evaluate different surfactants [qualitative]
– Cationic
14
The new EMA guidance
• Investigations related to the drug product should ensure immediate release properties and prove similarity between the investigative products, i.e. test and reference have a similar in vitro dissolution considering physiologically relevant experimental pH conditions.
• Polysorbates (Tween™) • Sodium dodecyl sulfate (sodium lauryl sulfate) • Lauryl dimethyl amine oxide • Cetyltrimethylammonium bromide (CTAB) • Polyethoxylated alcohols • Polyoxyethylene sorbitan • Octoxynol (Triton X100™) • N, N–dimethyldodecylamine– N–oxide • Hexadecyltrimethylammonium bromide (HTAB)
– Quats will ion pair with carboxylic acids at 2 pH’s units above pKa
13
Specific problems with SLS
• Use in combination only with Sodium Phosphate for 6.8 pH not Potassium Phosphate—precipitates at room temp
5
Poorly soluble drugs using surfactants [USP]
Estradiol/norgestimate (1mg/0.09mg) Ethinyl Estradiol/Norgestrel Amiodarone HCl (Test 2) Dicumerol Levonorgestrel Glyburide [non-micronized] Metolazone Tolcapone Tamsulosin HCl 0.3% SLS in water Water with 5 ppm of Tween 80 Acetate Buffer, pH 4.0, with 1% Tween 80 Basket 100 rpm, 1000 mL 0.1 TRIS buffer pH 9.0, 0.1 N HCl with 0.1% SLS Paddle 75rpm. 900ml., 0.5% CTAB in pH 9.0 borate buffer Paddle 75rpm, 900 mL 2.0% SLS/Water, Borate Buffer, pH 6.8 with 1% SLS 0-2 hours: 0.003% polysorbate 80, pH 1.2 2-8 hours: phosphate buffer, pH 7.2
• Polyoxyl 10 lauryl ether • Brij 721™ • Bile salts (sodium deoxycholate, sodium cholate) • Polyoxyl castor oil (Cremophor™) • Nonylphenol ethoxylate (Tergitol™) • Cyclodextrins • Lecithin • Methylbenzethonium chloride (Hyamine™)
15
Combination products
16
Combination products
• There are two meanings of combination products
– One or more active ingredient – A combination drug and device [considered under special dosage forms]
• These may present a significant challenge
• For multiple actives a single dissolution test should be aimed for.
USP
• ….aqueous solutions may contain a percentage of a surfactant (e.g. SLS, polysorbate or lauryldimethylamine oxide) . The need for surfactants and the concentrations used can be justified by showing profiles at several different concentrations.
– However, respective results are not an acceptable way to establish an in vitro/in vivo correlation.
• The pH conditions to be employed are at least pH 1.2, 4.5, and 6.8. Additional investigations may be required at pH values in which the drug substance has minimum solubility. • The use of any surfactant is strictly discouraged.
Dissolution 54mg Fenofibrate tablet 75 rpm
http://www.aapspharmscitech.org/
AAPS pharm sci tech 2006;7(2) Art33
8
Poorly water soluble drugs: Surfactants
Medium Sol mcg/ml DI Water 0.8 0.72% SLS 195 1.44% SLS 446 2.16% SLS 728 2% Tween 80 134
9
Valdecoxib dissolution
2.0% SLS 1.5% SLS 1.0% SLS 0.5%SLS 0.2% SLS
Worrying because the rate of dissolution does not really change, only the amount dissolved
10
Ketoprofen dissolution profile
11
Surfactants used in dissolution for PWSDS
BCS guidance, solubility is high if more than 160/250=0.64 mg/mLis soluble across pH range 1-7.5 Solubility based on 250ml volume
Having no ionizable groups, fenofibrate solubility is not 7 influenced by changes of the pH of the dissolution medium
– Increased wetting may give much higher dissolution than would be achieved in the GIT
• Be aware of chemical effects with ionic surfactants
– Sulphonic acid salts will ion-pair with amines at most pH’s
• All such methods have moved to aqueous media using surfactants*
*But now alcoholic medium is used to prove absence of dose dumping3
Development steps for PWSDs
• Old methods, including Pharmacopeial methods used organic solvents
– Carbamazepine
– Danazol [IPA/0.1N HCl:4/10] – Chlorthalidone
• These created extreme artifacts and had no biological significance
– Anionic
– Non-ionic
Evaluate different surfactants [quantitative]
4
Official Statements
FDA
• A dissolution medium containing surfactant can better simulate the environment of the gastrointestinal tract than a medium containing organic solvents or other nonphysiological substances, making the dissolution test conditions more useful in evaluating drug quality.