Dapsone
General Notices
(Ph. Eur. monograph 0077)
C12H12N2O2S248.380-08-0
Action and use
Folic acid synthesis inhibitor; treatment of leprosy.
Preparation
Dapsone Tablets
Ph Eur
DEFINITION
Dapsone contains not less than 99.0 per cent and not more than the equivalent of 101.0 per
cent of 4,4-sulfonyldianiline, calculated with reference to the dried substance.
CHARACTERS
A white or slightly yellowish-white, crystalline powder, very slightly soluble in water, freely
soluble in acetone, sparingly soluble in alcohol. It dissolves freely in dilute mineral acids.
IDENTIFICATION
A. Melting point (2.2.14): 175 C to 181 C.
B. Dissolve 50.0 mg in methanol R and dilute to 100.0 mL with the same solvent. Dilute 1.0
mL of this solution to 100.0 mL with methanol R. Examined between 230 nm and 350 nm
(2.2.25), the solution shows 2 absorption maxima, at 260 nm and 295 nm. The specific
absorbances at these maxima are 700 to 760 and 1150 to 1250, respectively.
C. Examine the chromatograms obtained in the test for related substances. The principal
spot in the chromatogram obtained with test solution (b) is similar in position, colour and size to
the principal spot in the chromatogram obtained with reference solution (a).
TESTS
Related substances
Examine by thin-layer chromatography (2.2.27), using silica gel G R as the coating substance.
Test solution (a)Dissolve 0.10 g of the substance to be examined in methanol R and dilute to
10 mL with the same solvent.
Test solution (b)Dilute 1 mL of test solution (a) to 10 mL with methanol R.
Reference solution (a)Dissolve 10 mg of dapsone CRS in methanol R and dilute to 10 mL
with the same solvent.
Reference solution (b)Dilute 1 mL of test solution (b) to 10 mL with methanol R.
Reference solution (c)Dilute 2 mL of reference solution (b) to 10 mL with methanol R.
Apply separately to the plate 1 L of test solution (b), 1 L of reference solution (a), 10 L of
test solution (a), 10 L of reference solution (b) and 10 L of reference solution (c). Develop in
an unsaturated tank over a path of 15 cm using a mixture of 1 volume of concentrated
ammonia R, 6 volumes of methanol R, 20 volumes of ethyl acetate R and 20 volumes of
heptane R. Allow the plate to dry in air. Spray the plate with a 1 g/L solution of 4dimethylaminocinnamaldehyde R in a mixture of 1 volume of hydrochloric acid R and 99
volumes of alcohol R. Examine in daylight. Any spot in the chromatogram obtained with test
solution (a), apart from the principal spot, is not more intense than the spot in the
chromatogram obtained with reference solution (b) (1.0 per cent) and not more than 2 such
spots are more intense than the spot in the chromatogram obtained with reference solution (c)
(0.2 per cent).
Loss on drying (2.2.32)
Not more than 1.5 per cent, determined on 1.000 g by drying in an oven at 105 C.
Sulfated ash (2.4.14)
Not more than 0.1 per cent, determined on 1.0 g.
ASSAY
Dissolve 0.100 g in 50 mL of dilute hydrochloric acid R. Carry out the determination of primary
aromatic amino-nitrogen (2.5.8).
1 mL of 0.1 M sodium nitrite is equivalent to 12.42 mg of C12H12N2O2S.
STORAGE
Store protected from light.
Ph Eur
Dapsone Tablets
General Notices
Action and use
Folic acid synthesis inhibitor; treatment of leprosy.
DEFINITION
Dapsone Tablets contain Dapsone.
The tablets comply with the requirements stated under Tablets and with the following
requirements.
Content of dapsone, C12H12N2O2S
95.0 to 105.0% of the stated amount.
IDENTIFICATION
A. Shake a quantity of the powdered tablets containing 0.1 g of Dapsone with 20 mL of
acetone, filter and evaporate the filtrate to dryness. The infrared absorption spectrum of the
residue, Appendix II A, is concordant with the reference spectrum of dapsone (RS 084).
B. In the test for Related substances, the principal spot in the chromatogram obtained with
solution (2) is similar in position, colour and size to that in the chromatogram obtained with
solution (5).
TESTS
Dissolution
Comply with the requirements for Monographs of the British Pharmacopoeia in the dissolution
test for tablets and capsules, Appendix XII B1.
TEST CONDITIONS
(a) Use Apparatus 1, rotating the basket at 100 revolutions per minute.
(b) Use 900 mL of 0.1M hydrochloric acid , at a temperature of 37, as the medium.
PROCEDURE
(1) After 45 minutes withdraw a 20 mL sample of the medium. To a volume of the filtered
sample expected to contain 0.1 mg of Dapsone add 1 mL of a freshly prepared 0.5% w/v
solution of sodium nitrite, and allow to stand for 3 minutes. Add 1.5 mL of a 1% w/v solution of
sulfamic acid , allow to stand for 3 minutes, add 2.5 mL of a freshly prepared 0.2% w/v solution
of N-(1-naphthyl)-ethylenediamine dihydrochloride in 0.1M hydrochloric acid and dilute to 20
mL with 1M hydrochloric acid (solution A). Carry out the procedure at the same time and in the
same manner using a volume of 0.1M hydrochloric acid equal to that of the filtered sample and
beginning at the words 'add 1 mL of a freshly prepared 0.5% w/v solution of sodium nitrite...'
(solution B). Allow solutions A and B to stand for at least 2 minutes and measure the
absorbance of solution A at the maximum at 538 nm, Appendix II B, using solution B in the
reference cell.
(2) Repeat the operation using a solution containing 0.1 mg of dapsone BPCRS in a volume
of 0.1M hydrochloric acid equal to that of the filtered sample and beginning at the words 'add 1
mL of a freshly prepared 0.5% w/v solution of sodium nitrite ...' and using solution B in the
reference cell.
DETERMINATION OF CONTENT
Calculate the total content of dapsone, C 12H12N2O2S, in the medium from the absorbances
obtained and using the declared content of C12H12N2O2S in dapsone BPCRS.
Related substances
Carry out the method for thin-layer chromatography, Appendix III A, using the following
solutions.
(1) Shake a quantity of the powdered tablets containing 0.1 g of Dapsone with 10 mL of
methanol and filter.
(2) Dilute 1 volume of solution (1) to 10 volumes with methanol .
(3) Dilute 1 volume of solution (2) to 10 volumes with methanol .
(4) Dilute 1 volume of solution (3) to 5 volumes with methanol .
(5) 0.1% w/v of dapsone BPCRS in methanol .
CHROMATOGRAPHIC CONDITIONS
(a) Use a TLC silica gel G plate.
(b) Use the mobile phase as described below.
(c) Apply 10 L of each of solutions (1), (3) and (4) and 1 L of each of solutions (2) and (5).
(d) Develop the plate to 15 cm in an unsaturated tank.
(e) After removal of the plate, dry in air, spray with a 0.1% w/v solution of 4dimethylaminocinnamaldehyde in a mixture of 1 volume of hydrochloric acid and 99 volumes of
ethanol (96%) and examine in daylight.
MOBILE PHASE
1 volume of 13.5M ammonia, 6 volumes of methanol , 20 volumes of ethyl acetate and 20
volumes of n-heptane.
LIMITS
Any secondary spot in the chromatogram obtained with solution (1) is not more intense that the
spot in the chromatogram obtained with solution (3) (1%) and not more than two such spots are
more intense than the spot in the chromatogram obtained with solution (4) (0.2%).
ASSAY
Weigh and powder 20 tablets. Dissolve a quantity of the powder containing 0.25 g of Dapsone
in a mixture of 15 mL of water and 15 mL of 2M hydrochloric acid , add 3 g of potassium
bromide, cool in ice and titrate slowly with 0.1M sodium nitrite VS, stirring constantly and
determining the end point electrometrically. Each mL of 0.1 M sodium nitrite VS is equivalent to
12.42 mg of C12H12N2O2S.
SC I E. Dissolution Testing of Solid Oral Dosage Forms
This section provides information on the pharmacopoeial dissolution test and guidance on its
function and application in individual monographs of the British Pharmacopoeia for tablets and
capsules.
1. Harmonisation
1.1 The dissolution test for solid oral dosage forms in Appendix XII B1 of the British
Pharmacopoeia is that of the European Pharmacopoeia (Ph. Eur. method 2.9.3). It is a
harmonised text prepared by the Pharmacopoeial Discussion Group (PDG). The PDG is
comprised of representatives of the European Pharmacopoeia, Japanese Pharmacopoeia and
the United States Pharmacopeia. Although the test is largely harmonised, some regional
differences remain.
1.2 It is not the intention of the British Pharmacopoeia to apply retrospectively the
harmonised test conditions and acceptance criteria to BP monographs or to change unilaterally
specifications for existing products. Appendix XII B1 contains a section entitled Monographs of
the British Pharmacopoeia which provides requirements for monographs for tablets and
capsules of the BP published prior to 2008. Taking account of permissible assay ranges and
content uniformity, this pharmacopoeial (that is, shelf-life) dissolution requirement is considered
to offer an acceptable degree of assurance of 'complete dissolution'. The choice of a time is, of
necessity, somewhat arbitrary but 45 minutes is considered satisfactory for the majority of
conventional-release (non-modified-release) products.
2. Apparatus
2.1 Four types of apparatuses are now described in the British and European
Pharmacopoeias; the basket, the paddle, the reciprocating cylinder and the flow- through cell.
The descriptions are concordant with those published in the United States Pharmacopeia
(USP).
2.2 Of the two established apparatuses (basket and paddle) the paddle is now the apparatus
of choice for many preparations. However, where a published test uses the basket, work to
validate a change to the paddle method is not contemplated. The reciprocating cylinder is
useful for pH profiling studies while the flow-through cell may be appropriate for preparations of
poorly soluble active ingredients (see Annex).
3. Test conditions and acceptance criteria
3.1 Test conditions The harmonised test conditions included in Appendix XII B1 will be
applied to all new monographs of the British Pharmacopoeia. It is not the intention of the British
Pharmacopoeia Commission to apply these criteria retrospectively to existing monographs.
Where an individual monograph prescribes the use of the requirements stated under
Monographs of the British Pharmacopoeia in Appendix XII B1, the following conditions using
the basket or paddle apparatus are preferred.
rotation speed:100 rpm (basket), 50 rpm (paddle)
dissolution medium volume: 900 mL
dissolution medium composition: aqueous, commonly 0.1 M hydrochloric acid or
phosphate buffers of pH 6.8 to 7.6
number of units tested: 6 (plus 6, if a retest is required).
The number of units tested is specified in Appendix XII B1; other conditions are specified in
the relevant individual monographs.
In situations where it has been demonstrated that the harmonised criteria are not applicable
(e.g. low solubility preparations, 'coning' of material in the vessel, low concentration of analyte),
modifications may be made to the test conditions, such as, adding a surfactant, increasing the
paddle rotation speed or using a modified vessel and reducing the volume of dissolution
medium used.
3.2 Acceptance criteria For new monographs for conventional-release preparations, unless
otherwise stated, the harmonised acceptance criteria ("Q" values) in Appendix XII B1 should be
applied. For monographs published prior to the BP 2008, the established BP criteria using
either the basket or the paddle apparatus are specified under 'Monographs of the British
Pharmacopoeia' in Appendix XII B1.
3.3 The schematic diagram outlines which limits to apply in each case (Fig. SCIE- 1).
Figure SCIE-1
3.4 A list of those British Pharmacopoeia monographs that were published up to and
including the BP 2007 is provided below.
Acebutolol Capsules
Acebutolol Tablets
Acenocoumarol Tablets
Acetazolamide Tablets
Aciclovir Tablets
Dispersible Aciclovir Tablets
Alimemazine Tablets
Allopurinol Tablets
Aloxiprin Tablets
Aluminium Hydroxide Tablets
Alverine Capsules
Amantadine Capsules
Amiloride Tablets
Aminoglutethimide Tablets
Aminophylline Tablets
Amiodarone Tablets
Amitriptyline Tablets
Amoxicillin Capsules
Ampicillin Capsules
Ascorbic Acid Tablets
Aspirin Tablets
Dispersible Aspirin Tablets
Effervescent Soluble Aspirin Tablets
Gastro-resistant Aspirin Tablets
Aspirin and Caffeine Tablets
Atenolol Tablets
Atropine Tablets
Azapropazone Capsules
Azapropazone Tablets
Azathioprine Tablets
Baclofen Tablets
Bendroflumethiazide Tablets
Benorilate Tablets
Benzatropine Tablets
Betahistine Dihydrochloride Tablets
Betamethasone Tablets
Betamethasone Sodium Phosphate Tablets
Gastro-resistant Bisacodyl Tablets
Bromocriptine Capsules
Bromocriptine Tablets
Brompheniramine Tablets
Bumetanide Tablets
Busulfan Tablets
Calcitriol Capsules
Calcium and Colecalciferol Tablets
Calcium and Ergocalciferol Tablets
Chewable Calcium Carbonate Tablets
Calcium Folinate Tablets
Calcium Gluconate Tablets
Effervescent Calcium Gluconate Tablets
Calcium Lactate Tablets
Captopril Tablets
Carbamazepine Tablets
Carbimazole Tablets
Cascara Tablets
Cefaclor Capsules
Cefadroxil Capsules
Cefalexin Capsules
Cefalexin Tablets
Cefradine Capsules
Cefuroxime Axetil Tablets
Chlorambucil Tablets
Chloramphenicol Capsules
Chlordiazepoxide Capsules
Chlordiazepoxide Hydrochloride Tablets
Chloroquine Phosphate Tablets
Chloroquine Sulfate Tablets
Chlorphenamine Tablets
Chlorpromazine Tablets
Chlorpropamide Tablets
Chlortalidone Tablets
Choline Theophyllinate Tablets
Cimetidine Tablets
Ciprofloxacin Tablets
Clemastine Tablets
Clindamycin Capsules
Clobazam Capsules
Clofazimine Capsules
Clofibrate Capsules
Clomethiazole Capsules
Clomifene Tablets
Clomipramine Capsules
Clonidine Tablets
Co-amilofruse Tablets
Co-amilozide Tablets
Co-amoxiclav Tablets
Co-beneldopa Capsules
Dispersible Co-beneldopa Tablets
Co-careldopa Tablets
Co-codamol Tablets
Effervescent Co-codamol Tablets
Co-codaprin Tablets
Dispersible Co-codaprin Tablets
Co-danthrusate Capsules
Codeine Phosphate Tablets
Codergocrine Tablets
Co-dydramol Tablets
Co-fluampicil Capsules
Colchicine Tablets
Colecalciferol Tablets
Colistin Tablets
Co-magaldrox Tablets
Co-proxamol Tablets
Cortisone Tablets
Co-tenidone Tablets
Co-triamterzide Tablets
Co-trimoxazole Tablets
Dispersible Co-trimoxazole Tablets
Paediatric Co-trimoxazole Tablets
Cyanocobalamin Tablets
Cyclizine Tablets
Cyclopenthiazide Tablets
Cyclophosphamide Tablets
Cyproheptadine Tablets
Cyproterone Tablets
Dapsone Tablets
Demeclocycline Capsules
Desipramine Tablets
Dexamethasone Tablets
Dexamfetamine Tablets
Dextromoramide Tablets
Dextropropoxyphene Capsules
Diazepam Tablets
Diazoxide Tablets
Dichlorophen Tablets
Dicycloverine Tablets
Diethylcarbamazine Tablets
Diethylstilbestrol Tablets
Diflunisal Tablets
Digitoxin Tablets
Digoxin Tablets
Dihydrocodeine Tablets
Diloxanide Tablets
Dimenhydrinate Tablets
Dipipanone and Cyclizine Tablets
Dipyridamole Tablets
Disopyramide Capsules
Disopyramide Phosphate Capsules
Disulfiram Tablets
Docusate Capsules
Domperidone Tablets
Dosulepin Capsules
Dosulepin Tablets
Doxepin Capsules
Doxycycline Capsules
Dispersible Doxycycline Tablets
Droperidol Tablets
Dydrogesterone Tablets
Enalapril Tablets
Ephedrine Hydrochloride Tablets
Ergocalciferol Tablets
Ergometrine Tablets
Ergotamine Sublingual Tablets
Erythromycin Estolate Capsules
Erythromycin Ethyl Succinate Tablets
Erythromycin Stearate Tablets
Gastro-resistant Erythromycin Tablets
Estradiol and Norethisterone Tablets
Estradiol and Norethisterone Acetate Tablets
Estramustine Phosphate Capsules
Estropipate Tablets
Ethambutol Tablets
Ethinylestradiol Tablets
Ethosuximide Capsules
Etodolac Capsules
Etodolac Tablets
Etoposide Capsules
Famotidine Tablets
Fenbufen Capsules
Fenbufen Tablets
Fenoprofen Tablets
Ferrous Fumarate Capsules
Ferrous Fumarate Tablets
Ferrous Fumarate and Folic Acid Tablets
Ferrous Gluconate Tablets
Ferrous Sulfate Tablets
Finasteride Tablets
Flavoxate Tablets
Flecainide Tablets
Flucloxacillin Capsules
Flucytosine Tablets
Fludrocortisone Tablets
Fluoxetine Capsules
Fluphenazine Tablets
Flurazepam Capsules
Flurbiprofen Tablets
Fluvoxamine Tablets
Folic Acid Tablets
Fosfestrol Tablets
Furosemide Tablets
Gemfibrozil Capsules
Gemfibrozil Tablets
Glibenclamide Tablets
Gliclazide Tablets
Glipizide Tablets
Gliquidone Tablets
Glyceryl Trinitrate Tablets
Griseofulvin Tablets
Guanethidine Tablets
Halibut-liver Oil Capsules
Haloperidol Capsules
Haloperidol Tablets
Hydralazine Tablets
Hydrochlorothiazide Tablets
Hydrocortisone Oromucosal Tablets
Hydroflumethiazide Tablets
Hydrotalcite Tablets
Hydroxycarbamide Capsules
Hydroxychloroquine Tablets
Hyoscine Butylbromide Tablets
Hyoscine Tablets
Ibuprofen Tablets
Imipramine Tablets
Indapamide Tablets
Indometacin Capsules
Indoramin Tablets
Inositol Nicotinate Tablets
Iopanoic Acid Tablets
Isoniazid Tablets
Isosorbide Dinitrate Tablets
Isosorbide Dinitrate Sublingual Tablets
Isosorbide Mononitrate Tablets
Isotretinoin Capsules
Isradipine Tablets
Ketoprofen Capsules
Labetalol Tablets
Lacidipine Tablets
Levodopa Capsules
Levodopa Tablets
Levomepromazine Tablets
Levonorgestrel Tablets
Levonorgestrel and Ethinylestradiol Tablets
Levothyroxine Tablets
Lincomycin Capsules
Liothyronine Tablets
Lisinopril Tablets
Lithium Carbonate Tablets
Lofepramine Tablets
Lomustine Capsules
Loperamide Capsules
Loprazolam Tablets
Lorazepam Tablets
Lormetazepam Tablets
Lymecycline Capsules
Compound Magnesium Trisilicate Tablets
Mebeverine Tablets
Mefenamic Acid Capsules
Mefenamic Acid Tablets
Megestrol Tablets
Meloxicam Tablets
Melphalan Tablets
Menadiol Phosphate Tablets
Meptazinol Tablets
Mepyramine Tablets
Mercaptopurine Tablets
Metformin Tablets
Methadone Tablets
Methotrexate Tablets
Methylcellulose Tablets
Methyldopa Tablets
Methylphenobarbital Tablets
Methylprednisolone Tablets
Methysergide Tablets
Metoclopramide Tablets
Metoprolol Tartrate Tablets
Metronidazole Tablets
Metyrapone Capsules
Mexiletine Capsules
Mianserin Tablets
Minocycline Tablets
Mitobronitol Tablets
Morphine Tablets
Moxisylyte Tablets
Nabumetone Tablets
Naftidrofuryl Capsules
Nalidixic Acid Tablets
Naproxen Tablets
Neomycin Tablets
Neostigmine Tablets
Niclosamide Tablets
Nicotinamide Tablets
Nicotinic Acid Tablets
Nicotinyl Alcohol Tablets
Nifedipine Capsules
Nimodipine Tablets
Nitrazepam Tablets
Nitrofurantoin Tablets
Norethisterone Tablets
Norfloxacin Tablets
Norgestrel Tablets
Nortriptyline Capsules
Nortriptyline Tablets
Nystatin Tablets
Orciprenaline Tablets
Orphenadrine Hydrochloride Tablets
Oxazepam Tablets
Oxprenolol Tablets
Oxybutynin Tablets
Oxymetholone Tablets
Oxytetracycline Capsules
Oxytetracycline Tablets
Paracetamol Tablets
Dispersible Paracetamol Tablets
Soluble Paracetamol Tablets
Paroxetine Tablets
Penicillamine Tablets
Pentazocine Capsules
Pentazocine Tablets
Pentobarbital Tablets
Perphenazine Tablets
Pethidine Tablets
Phenelzine Tablets
Phenindione Tablets
Phenobarbital Tablets
Phenobarbital Sodium Tablets
Phenoxybenzamine Capsules
Phenoxymethylpenicillin Tablets
Phenytoin Capsules
Phenytoin Tablets
Phytomenadione Tablets
Pimozide Tablets
Pindolol Tablets
Piperazine Phosphate Tablets
Piroxicam Capsules
Pizotifen Tablets
Poldine Tablets
Polythiazide Tablets
Effervescent Potassium Chloride Tablets
Potassium Iodate Tablets
Pravastatin Tablets
Prazosin Tablets
Prednisolone Tablets
Primidone Tablets
Probenecid Tablets
Procainamide Tablets
Prochlorperazine Tablets
Prochlorperazine Buccal Tablets
Procyclidine Tablets
Proguanil Tablets
Promazine Tablets
Promethazine Hydrochloride Tablets
Promethazine Teoclate Tablets
Propantheline Tablets
Propranolol Tablets
Propylthiouracil Tablets
Protriptyline Tablets
Pseudoephedrine Tablets
Pyrazinamide Tablets
Pyridostigmine Tablets
Pyridoxine Tablets
Pyrimethamine Tablets
Quinidine Sulfate Tablets
Quinine Bisulfate Tablets
Quinine Sulfate Tablets
Ramipril Capsules
Ramipril Tablets
Ranitidine Tablets
Rifampicin Capsules
Ritodrine Tablets
Salbutamol Tablets
Selegiline Tablets
Senna Tablets
Compound Sodium Bicarbonate Tablets
Sodium Chloride Tablets
Sodium Fluoride Tablets
Sodium Valproate Tablets
Sotalol Tablets
Spironolactone Tablets
Stanozolol Tablets
Sulfasalazine Tablets
Sulfinpyrazone Tablets
Sulindac Tablets
Sulpiride Tablets
Sumatriptan Tablets
Tamoxifen Tablets
Temazepam Tablets
Tenoxicam Tablets
Terbutaline Tablets
Terfenadine Tablets
Tetracycline Capsules
Tetracycline Tablets
Thiamine Tablets
Tiabendazole Tablets
Timolol Tablets
Tioguanine Tablets
Alpha Tocopheryl Succinate Tablets
Tolazamide Tablets
Tolbutamide Tablets
Tramadol Capsules
Tranexamic Acid Tablets
Tranylcypromine Tablets
Triamcinolone Tablets
Triamterene Capsules
Trifluoperazine Tablets
Trihexyphenidyl Tablets
Trimethoprim Tablets
Trimipramine Tablets
Triprolidine Tablets
Ursodeoxycholic Acid Capsules
Ursodeoxycholic Acid Tablets
Verapamil Tablets
Vigabatrin Tablets
Warfarin Tablets
Zuclopenthixol Tablets
Acepromazine Tablets [BP (Vet)]
Amoxicillin Tablets [BP (Vet)]
Ampicillin Tablets [BP (Vet)]
Chlortetracycline Tablets [BP (Vet)]
Cobalt Depot-tablets [BP (Vet)]
Co-trimazine Tablets [BP (Vet)]
Etamiphylline Tablets [BP (Vet)]
Lincomycin Tablets [BP (Vet)]
Methyltestosterone Tablets [BP (Vet)]
Phenylbutazone Tablets [BP (Vet)]
Piperazine Adipate Tablets [BP (Vet)]
Piperazine Citrate Tablets [BP (Vet)]
Sulfadimidine Tablets [BP (Vet)]
Sulfadoxine and Trimethoprim Tablets [BP (Vet)]
Tylosin Tablets [BP (Vet)]
3.5 Standardised conditions and limits are considered appropriate for a pharmacopoeial test
that is intended to apply to monographs covering products from different manufacturers. It
might be argued that non-standardised conditions and limits would be more discriminatory but
'tailor-made' test conditions and limits may introduce product bias and may discriminate
unnecessarily between products that are equally acceptable from a clinical view-point. Similarly
with sufficient manipulation of the test conditions, dissolution of almost any product can be
achieved. Ideally the test should reflect clinically significant differences in bioavailability arising
from differences in dissolution in such a way that clinically acceptable formulations will pass
whereas clinically unacceptable formulations will fail.
3.6 Another issue that has been considered in relation to test conditions and criteria is that of
multiple-point dissolution profiles as opposed to single-point dissolution tests. It has been
concluded that for conventional-release preparations such an extension of testing is not
generally necessary or appropriate for pharmacopoeial purposes.
4. Function
4.1 The ultimate objective of dissolution testing may be described as ensuring adequate and
reproducible bioavailability without recourse to routine in-vivo testing. On some occasions, this
may be achieved by dissolution testing of a particular product for which in vitro/in vivo
correlation has been demonstrated.
4.2 A more common objective of dissolution testing is to obtain information about the drug
release characteristics of a particular formulation or batch of product under standardised in
vitro testing conditions.
4.3 Dissolution testing may also be carried out during product development studies and is a
useful tool in optimising formulation and manufacturing parameters. It is usually required by the
Competent Authority as part of a marketing authorisation application.
4.4 Once a product is licensed, dissolution testing may be required routinely as part of
quality control to demonstrate consistency of manufacture before the release of each batch of
the finished product or, when necessary, to provide evidence to support changes in
manufacture such as minor changes in formulation or process, changes in site or changes in
immediate packaging materials.
5. Application
5.1 The British Pharmacopoeia Commission has not adopted a policy of universal application
of the dissolution test and, therefore, a dissolution requirement will not be included
automatically in every capsule and tablet monograph. The International Conference on
Harmonisation (ICH) guideline on Test Procedures and Acceptance Criteria for New Drug
Substances and New Drug Products (ICH Q6A) contains guidance on the application of
dissolution testing to drug products and this will be used as a basis for deciding whether to
include a dissolution test in an individual monograph.
5.2 As a general guideline, it is expected that all new monographs for conventional-release
capsules and tablets will contain a dissolution requirement except (i) where the solubility of the
active ingredient at 37 0.5 is high throughout the physiological pH range (dose/solubility
volume < 250 mL at pH 1.2 to 6.8); (ii) where the dissolution of the dosage form is greater than
80% in 15 minutes at pH 1.2, 4.0 and 6.8; (iii) where a relationship has been determined
between disintegration and dissolution, or when disintegration has been observed to be more
discriminatory than dissolution. In circumstances where conditions (i) to (iii) have been
satisfied, the dissolution test may be replaced by the disintegration test for tablets and
capsules, Appendix XII A1.
5.3 If challenged, a product would be expected to comply with the test for dissolution
specified in the individual monograph, or if none is specified, with the Test conditions and
acceptance criteria outlined in section 3.
5.4 Dissolution tests have been added to a considerable number of monographs in the
British Pharmacopoeia. While the objective is to include a 'standard' pharmacopoeial test
wherever appropriate, the circumstances for each preparation are considered individually in
consultation with the manufacturers. It should be appreciated, however, that the retrospective
addition of dissolution tests is not without its difficulties. The problems are most acute for those
well-established preparations that are manufactured by a wide range of companies, each with
its own dissolution specification. A pragmatic approach is being taken to developing
compromise test procedures in these circumstances.
6. Bioavailability and Bioequivalence
6.1 Compliance with the standard British Pharmacopoeia requirement for dissolution
provides an assurance that most of the active ingredient will be dissolved in a reasonable
amount of time when the preparation is subjected to mild agitation.
6.2 It should be noted that compliance with the pharmacopoeial dissolution test does not by
itself guarantee bioavailability and is not necessarily an adequate basis for judging
bioequivalence between preparations. Preparations having similar dissolution characteristics
may not be bioequivalent and vice versa.
7. Application of harmonised dissolution limits ("Q" values)
7.1 Since the harmonisation of the dissolution test through the Pharmacopoeial Discussion
Group and the adoption of harmonised dissolution criteria ("Q values") between the European,
United States and Japanese Pharmacopoeias, the BP Commission has received many queries
regarding the application of limits to dissolution tests.
7.2 As an aid to analysts several worked examples are provided as an illustrative guide
below.
7.3 An immediate-release tablet formulation has a limit of Q = 75%. Six units are tested.
Unit
1
2
3
4
5
6
Result (% of stated amount)
83
87
80
88
90
82
In order to pass S1, all units must be greater than or equal to (Q + 5)% (i.e. 80%). Hence, the
above batch passes at S1.
7.4 An immediate-release tablet formulation has a limit of Q = 75%. Six units are tested.
Unit
1
2
3
4
5
6
Result (% of stated amount)
77
87
70
88
90
82
Since units 1 and 3 are less than (Q+5)% (i.e. 80%), the batch fails at S1. A further six units
must then be tested.
Unit
7
8
9
10
11
12
Result (% of stated amount)
78
85
79
84
87
85
In order to pass S2, the mean of twelve units must be greater than or equal to Q and no unit
can be less than (Q 15)% (i.e. 60%). The mean of the twelve units is 83% so this passes at
S2 and, units 1 and 3, whilst failing at S1, are not less than (Q 15)%, so this batch passes at
S2.
7.4 An immediate-release tablet formulation has a limit of Q = 75%. Six units are tested.
Unit
1
2
3
4
5
6
Result (% of stated amount)
77
87
70
88
76
79
Since units 1, 3, 5 and 6 are less than (Q+5)% (i.e. 80%), the batch fails at S1. A further six
units must then be tested
Unit
7
8
9
10
11
12
Result (% of stated amount)
73
85
79
84
87
58
Because unit 12 is less than (Q 15)% (i.e. 60%) the batch fails at S2. A further twelve units
must then be tested.
Unit
13
14
15
16
17
18
19
20
21
22
23
24
Result (% of stated amount)
79
83
67
84
80
82
78
85
84
81
83
88
In order to pass S3, the mean of 24 units must be greater than or equal to Q , not more than
two units can be less than (Q 15)% (i.e. 60%) and no unit can be less than (Q 25)% (i.e.
50%). The mean of the 24 units is 80% so this passes at S3. Only unit 12 is less than (Q
15)% and none are less than (Q 25)% so this batch passes at S3.
7.6 An immediate-release capsule formulation has a limit of Q = 75%. Six units are tested.
Unit
1
2
3
4
5
6
Result (% of stated amount)
83
82
80
79
49
77
Since unit 5 is less than (Q 25)% (i.e. 50%), the batch would fail at S3. Testing further units
will not enable this batch to pass the test.
7.7 An immediate-release capsule formulation has a limit of Q = 75%. 24 units have been
tested.
Unit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
Result (% of stated amount)
76
82
80
79
70
77
65
69
77
73
68
71
79
65
70
72
67
83
63
68
74
71
75
70
All the units are greater than (Q 15)% (i.e. 60%), however; because the mean (73%) is
less than Q, this batch fails at S3.
