WO2015170237A1

WO2015170237A1 - Stable solifenacin composition

Info

Publication number: WO2015170237A1
Application number: PCT/IB2015/053239
Authority: WO
Inventors: Jaya Abraham; Sujay Rajhans; Sukanta CHATTERJEE; Devesh Bhatt
Original assignee: Torrent Pharmaceuticals Limited
Priority date: 2014-05-05
Filing date: 2015-05-04
Publication date: 2015-11-12

Abstract

The present invention provides a stable solid oral pharmaceutical composition comprising solifenacin and a stabilizer selected from tartaric acid, fumaric acid, maleic acid & succinic acid; wherein solifenacin is in a substantially amorphous form.

Description

STABLE SOLIFENACIN COMPOSITION FIELD OF INVENTION

The present invention provides a stable solid oral pharmaceutical composition comprising solifenacin and a stabilizer selected from tartaric acid, fumaric acid, maleic acid & succinic acid; wherein solifenacin is in a substantially amorphous form and a process for the preparation of said pharmaceutical composition. BACKGROUND

Solifenacin succinate is a muscarinic receptor antagonist. Solifenacin succinate has a chemical name butanedioic acid, compound with 1 (S)-3(R)-1- azabicyclo[2.2.2]oct- 3-yl 3,4-dihydro-l -phenyl-2(l H)-isoquinolinecarboxylate (1 : 1) having an empirical formula C23H26N2O2.C4H6O4 and a molecular weight of 480.55., The structural formula for solifenacin succinate is Formula 1.

(Formulal) Solifenacin succinate is a white to pale-yellowish-white crystal or crystalline powder. It is freely soluble at room temperature in water, glacial acetic acid, dimethyl sulfoxide, and methanol.

Solifenacin succinate is available in the market from Astellas Pharmaceuticals Inc. under the name VESICARE^® , in two strengths, 5 mg and 10 mg of solifenacin succinate, and formulated as tablets for oral administration. In addition to the active ingredient solifenacin succinate, each VESICARE tablet also contains the following inactive excipients: lactose monohydrate, corn starch, hypromellose 2910, magnesium stearate, talc, polyethylene glycol 8000 and titanium dioxide with yellow ferric oxide (5 mg) or red ferric oxide (10 mg). Solifenacin succinate is approved for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency and urinary frequency.

It is well known in the art that, degradation of a drug substance in a formulation generally involves for example redox reaction, hydrolysis reaction, racemization, photo degradation and polymeric degradation. Solifenacin has been found to be highly unstable in the formulation and tends to generate impurities. It has also been found that generation of an amorphous solifenacin during a manufacturing process of the drug product is the main cause of the degradation of the active pharmaceutical ingredient over time. EPl 728791 discloses a stable pharmaceutical composition comprising the crystal of solifenacin wherein the amorphous content is 77 % or less showing no influence on drug product stability. This patent application also discloses a stable pharmaceutical composition comprising an inhibitor for amorphization, because the amorphous form of solifenacin tends to degrade by oxidation or the like and generate N-Oxide impurity.

EP2500013 discloses a stable pharmaceutical composition comprising crystalline solifenacin and excipient granules wherein excipient granules do not contain solifenacin.

EP2778167 discloses a pharmaceutical composition that has improved storage stability with respect to dissolution comprising at least 2% w/w disintegrant(s) and solifenacin or pharmaceutical acceptable salt thereof which is substantially free of crystalline form and is free of degradation impurities, characterized in that the composition is prepared by wet granulation. Further it discloses a stable formulation comprising amorphous solifenacin succinate free of stabilizers and antioxidants.

WO2008128028 discloses a stable composition containing the amorphous form of solifenacin, and a process of manufacturing the composition, wherein solifenacin is stabilized using anti oxidant and polymeric substance.

US20100273825 discloses a solid pharmaceutical composition comprising an amorphous form of solifenacin and a stabilizer selected from the group consisting of citric acid or a pharmaceutically acceptable salt (excluding a calcium salt) thereof, sodium pyrosulfite, and a pharmaceutically acceptable salt of ethylenediaminetetraacetic acid.

WO2009012987 discloses a pharmaceutical composition comprising solifenacin and a stabilizer selected from HPMC, Lactose, mannitol and the ratio of stabilzer to solifenacin thereof based on parts per weight is at least about 2: 1

WO2006070735 discloses a stable particulate pharmaceutical composition, comprising solifenacin and a binder having an action of stabilizing solifenacin or a salt thereof.

Hence, there is a challenge to stabilize solifenacin in the formulation and more particularly in an amorphous form. Various techniques are tried in the prior art to stabilize amorphous solifenacin.

However, approaches for stabilizing solifenacin in an amorphous form has yet not resulted in a stable composition and hence solifenacin when marketed in an amorphous form has been protected using special packaging with nitrogen flushing to prevent the degradation. Thus, there still exists a need in the art to provide the economically viable process which results in a stable composition even in standard packaging such as blister and HDPE bottle during shelf life under normal storage conditions.

BRIEF DESCRIPTION OF DRAWINGS

Fig 1 illustrates an overlay of the XRPD pattern of solifenacin succinate, placebo and tablet of Ex.9.

SUMMARY OF THE INVENTION

One object of the present invention provides a stable solid oral pharmaceutical composition comprising solifenacin and a stabilizer selected from tartaric acid, fumaric acid, maleic acid & succinic acid; wherein solifenacin is in a substantially amorphous form.

In another object, present invention provides a stable pharmaceutical composition comprising solifenacin having less than 0.1% of N-oxide impurity during shelf life, preferably 0.06%, more Preferably solifenacin N-oxide impurity is 0.03%. Most preferably solifenacin N-oxide impurity is 0.01% under normal storage condition.

One object of the present invention is to provide a stable solid oral pharmaceutical composition comprising solifenacin, prepared by a process comprising steps of:

(a) preparing a solution comprising a stabilizer selected from tartaric acid, fumaric acid, maleic acid & succinic acid and antioxidant and solvent;

(b) granulating the mixture comprising solifenacin , water soluble polymer & optionally other pharmaceutical excipient with solution prepared in step (a);

(c) optionally, drying the granules prepared in step (b);

(d) mixing granules prepared in step (b) or (c) optionally with diluent and lubricant;

(e) preparing a pharmaceutical composition from the mixture or blend of step (d). Another object of present invention is to provide a process for the preparation of a stable solid oral pharmaceutical composition comprising steps of:

(a) preparing a solution comprising antioxidant, a stabilizer selected from tartaric acid, fumaric acid, maleic acid & succinic acid and solvent;

(b) granulating the mixture comprising solifenacin, water soluble polymer and one or more diluent with solution prepared in step a);

(c) optionally, drying the granules prepared in step (b);

(e) preparing a pharmaceutical composition from the mixture or blend of step (d). DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a stable pharmaceutical composition comprising solifenacin and a stabilizer selected from tartaric acid, fumaric acid, maleic acid & succinic acid and a process for the preparation of said pharmaceutical composition.

The present invention also provides a stable pharmaceutical composition comprising solifenacin and a stabilizer selected from tartaric acid, fumaric acid, maleic acid & succinic acid, wherein solifenacin is in a substantially amorphous form.

Further, the present invention also provides a stable pharmaceutical composition comprising solifenacin having less than 0.1% of N-oxide impurity during shelf life, preferably 0.06%, more Preferably solifenacin N-oxide impurity is 0.03%. Most preferably solifenacin N-oxide impurity is 0.01% under normal storage condition.

The term "amorphous" or "amorphous form" according to the invention refers that recognizable characteristic crystalline solifenacin peaks are not present in an X-ray powder diffraction. The term "substantially amorphous" according to the invention refers that pharmaceutical composition of the present invention comprises at least about 90 wt % of solifenacin is in an amorphous form, yet more preferably at least about 95 wt % and even more preferably at least about 99 wt % of solifenacin is in an amorphous form. In a most preferred embodiment, all or substantially all of the solifenacin is in an amorphous form.

The term "under normal storage conditions" according to the invention refers that the storage conditions at 40°C and 75% RH for minimum period of one month and/or till normal shelf life i. e 24-36 months.

The term "stabilizer" for solifenacin according to the invention refers that it is pharmaceutically acceptable and helps to stabilize an amorphous form of solifenacin. The use of the terms "a" and "an" and "the" and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Throughout this specification and the appended claims it is to be understood that the words "comprise", "have", "contain" and "include" and variations such as "comprises", "comprising", "having", "containing" "includes", "including" are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited. The term "Solifenacin" as used herein includes solifenacin or its isomers, its enantiomers, its racemates, its pharmaceutically acceptable salts or its polymorphs, or mixtures thereof. Preferably, "solifenacin" present in the composition according to present invention is solifenacin succinate. First embodiment of the invention provides a stable pharmaceutical composition comprising solifenacin prepared by a process comprising steps of:

(a) preparing a solution comprising a stabilizer selected from tartaric acid, maleic acid, fumaric acid & succinic acid , an antioxidant and solvent; (b) granulating the mixture comprising solifenacin, water soluble polymer & optionally other pharmaceutical excipient with solution prepared in step (a);

(c) optionally, drying the granules prepared in step (b);

(d) mixing granules prepared in step (b) or (c) with optionally diluent and lubricant;

(e) preparing a pharmaceutical composition from the mixture or blend of step (d).

Solution of step (a) comprising a stabilizer selected from tartaric acid, maleic acid, fumaric acid & succinic acid in purified water and an antioxidant in ethanol prepared by adding components in any order, preferably, solution of antioxidant in ethanol is prepared first and then stabilizer is dissolved in purified water.

A preferred embodiment of the invention provides a stable solid oral pharmaceutical composition comprising granulation of the mixture comprising solifenacin, water soluble polymer such as hydroxypropyl methyl cellulose or polyvinyl pyrrolidone, disintegrant such as pregelatinized starch and one or more diluent such as lactose monohydrate, microcrystalline cellulose by a granulating solution comprising stabilizer such as tartaric acid, succinic acid, maleic acid and fumaric acid, antioxidant such as butylated hydroxy toluene in Solvent.

Another embodiment of present invention provides a stable solid oral pharmaceutical composition comprising of solifenacin, stabilizer, antioxidant, binder, disintegrant and lubricant.

Another embodiment of the invention provides, a stable solid oral pharmaceutical composition comprising solifenacin; antioxidants selected from sodium hydrogen sulfite, tocopherol acetate, tocopherol, propyl gallate, Butyl hydroxy toluene, Butyl hydroxy anisole and stabilizers selected from tartaric acid, fumaric acid, succinic acid and maleic acid; wherein solifenacin is in a substantially amorphous form.

Yet another embodiment of the invention provides, a stable solid oral pharmaceutical composition comprising solifenacin; Butyl hydroxy toluene and stabilizer selected from tartaric acid, fumaric acid, succinic acid and maleic acid; wherein solifenacin is in a substantially amorphous form.

A most preferred embodiment of the invention provides, a stable solid oral pharmaceutical composition comprising solifenacin; Butyl hydroxy toluene and tartaric acid, wherein solifenacin is in a substantially amorphous form. A preferred embodiment of the invention provides a stable solid oral pharmaceutical composition comprising of 5% to 12% w/w of solifenacin, 0.01% to 4% w/w of stabilizer, 0.01% to 4 % w/w of antioxidant, 0.01% to 5% w/w of binder, 1% to 25% w/w of disintegrant & 0.1% to 5% w/w of lubricant of total weight of the composition.

Another embodiment of the invention provides a stable solid oral pharmaceutical composition comprising of 6.47% w/w of solifenacin, 3.24 % w/w of stabilizer selected from tartaric acid, succinic acid, maleic acid and fumaric acid, 0.26 % w/w of butylated hydroxy toluene, 2.59% w/w of hydroxypropyl methyl cellulose or polyvinyl pyrrolidone, 16.18% w/w of pregelatinized starch and 1.17 % w/w of magnesium stearate of total weight of the composition.

A preferred embodiment of the invention provides a stable solid oral pharmaceutical composition consisting of 6.47% w/w of solifenacin, 3.24 % w/w of tartaric acid, 0.26 % w/w of butylated hydroxytoluene, 2.59% w/w of hydroxypropyl methyl cellulose, 16.18% w/w of pregelatinized starch and 1.17 % w/w of magnesium stearate of total weight of the composition.

In a most preferred embodiment of the invention provides a stable solid oral pharmaceutical composition consisting of 6.47% w/w of solifenacin, 3.24 % w/w of tartaric acid, 0.26 % w/w of butylated hydroxytoluene, 1.29 % w/w of hydroxypropyl methyl cellulose, 8.09 % w/w of pregelatinized starch and 0.58 % w/w of magnesium stearate of total weight of the composition. Another embodiment of present invention provides a process for the preparation of a stable solid oral pharmaceutical composition of solifenacin comprising steps of: (a) preparing a solution comprising butylated hydroxy toluene in ethanol & tartaric acid in purified water;

(b) granulating the mixture comprising solifenacin, hydroxypropyl methyl cellulose pregelatinized starch, lactose monohydrate, with solution prepared in step a);

(c) optionally, drying the granules prepared in step (b);

(d) mixing granules prepared in step (b) or (c) with lactose monohydrate and magnesium stearate;

The order of steps in the process of preparation of pharmaceutical compositions according to present invention is for the purpose of representation only and should not limit the scope of the embodiments with respect to performance of steps in the mentioned sequence.

It was observed that composition of present invention were found stable with less than 0.1% of N-oxide impurity, even when packed in standard packaging material including blister or bottle packs; wherein special treatment for oxygen or moisture protection such as oxygen scavenger, desiccant or nitrogen flushing are not required.

Thus, another embodiment of present invention provides a stable solid oral pharmaceutical composition, wherein composition is packed in a container selected from blister pack or bottle pack. Blister pack is preferably selected from Alu-Alu, polyvinyl chloride and polystyrene. Bottle pack is preferably selected from high density polyethylene (HDPE), low density polyethylene (LDPE) and polyethylene terephthalate (PET). Pharmaceutical excipient according to present invention may comprise diluent, disintegrant, lubricant, antioxidant, stabilizer and the like.

Compositions according to present invention may optionally further comprises one or more glidant, binder, surfactant, flavoring agent, preservatives, and the like. Example and suitable amount of said optional excipient is known to a skilled person or as given m Handbook of pharmaceutical excipients (sixth edition, 2009).

A diluent according to present invention includes powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, starch, dibasic calcium phosphate, dibasic sodium phosphate, tribasic sodium phosphate; sugars such as dextrose, lactose, lactose monohydrate or sucrose; sugar alcohols such as mannitol, sorbitol, xylitol or erythritol; or mixtures thereof; most preferably diluent is lactose mono hydrate & microcrystalline cellulose. Pharmaceutical composition comprises diluent in the amount of 50-95% w/w of the total composition.

A disintegrant according to present invention includes calcium carboxymethyl cellulose and its salt including sodium or calcium salt, cross-linked carboxymethyl cellulose sodium, cross-linked carboxymethyl cellulose calcium, cross-linked polyvinyl pyrrolidone, sodium starch glycolate, pregelatinized starch, low substituted hydroxypropyl cellulose; or mixtures thereof, more preferably disintegrant is pregelatinized starch Pharmaceutical composition comprises disintegrant in the amount of 1 - 25% w/w of the total composition.

A binder according to present invention includes polyvinyl alcohol, starch, pregelatinised starch; cellulose derivatives such as cellulose powder, microcrystalline cellulose, hydroxypropyl methylcellulose, ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, gelatin, zein, polymethacrylates, sodium alginate, gums, synthetic resins or mixtures thereof; more preferably binder is hydroxypropylmethyl cellulose. Pharmaceutical composition comprises binder in the amount of 0.01-5% w/w of the total composition. A lubricant according to present invention includes talc, metallic stearate such as magnesium stearate, calcium stearate, zinc stearate; colloidal silicon dioxide, finely divided silicon dioxide, stearic acid, hydrogenated vegetable oil, glyceryl palmitostearate, glyceryl monostearate, glyceryl behenate, sodium stearyl fumarate, magnesium trisilicate or mixtures thereof; more preferably lubricant is magnesium stearate. Pharmaceutical composition comprises lubricant in the amount of 0.1-5% w/w of the total composition.

An antioxidant according to present invention includes sodium hydrogen sulfite, tocopherol acetate, tocopherol, propyl gallate, Butyl hydroxy toluene, Butyl hydroxy anisole; more preferably antioxidant is Butyl hydroxy toluene. Pharmaceutical composition comprises antioxidant in the amount of 0.01- 4% w/w of the total composition. A stabilizer according to present invention includes tartaric acid, maleic acid, fumaric acid, succinic acid and the like or mixture thereof, preferably tartaric acid, maleic acid, fumaric acid, most preferably tartaric acid. Pharmaceutical composition comprises stabilizer in the amount of 0.01- 4 % w/w of the total composition. A water soluble polymer according to present invention includes hydroxypropylmethylcellulose, polyvinylpyrrolidone, methylcellulose and the like. Pharmaceutical composition comprises water soluble polymer in the amount of 0.1- 5 % w/w of the total composition. Water soluble polymers as defined herein can also act as a binder in the present composition.

A Suitable solvent according to present invention includes organic, aqueous, or a mixture thereof. Organic solvents may be aliphatic alcohols such as methanol, ethanol, n-propanol, and isopropanol; aliphatic ketones such as acetone and methyl ethyl ketone; aliphatic carboxylic esters such as ethyl acetate; aromatic hydrocarbons such as toluene and xylene; aliphatic hydrocarbons such as hexane; aliphatic nitriles such as acetonitrile; chlorinated hydrocarbons such as dichloromethane; aliphatic sulfoxides such as dimethyl sulfoxide; and the like, as well as mixtures comprising at least one of the foregoing organic solvents. Aqueous solvents include solvent comprising water, water and/or a water-miscible organic solvent such as a lower alcohol, acetonitrile, tetrahydrofuran, dimethylacetamide, dimethyl formamide, and the like. Combination of various solvents can also be used. Most preferable is water & ethanol.

A pharmaceutical composition according to present invention may optionally comprise a coating.

Coating according to present invention may be functional or non-functional coating, preferably coating is non-functional coating. Non-functional coating comprises a film forming polymer and one or more excipients suitable for said coating.

A coating can be applied using the materials and methods known to a person skilled in the art. Examples of film coating material includes Opadry® which is Colorcon's customized, one-step film coating system which combines polymer, plasticizer, opacifier, and pigment, as required, in a dry concentrate.

A pharmaceutical composition according to present invention is a solid composition for immediate release for oral administration and it can be in the form of tablet or capsule. Preferably, said composition is in the form of tablet for oral administration.

The invention will be further illustrated by the following examples, however, without restricting its scope to these embodiments.

Examples Examples 1 to 4

Process:

(a) dry mixture of solifenacin succinate, pregelatinized starch, lactose monohydrate , microcrystalline cellulose and hydroxypropylmethyl cellulose was prepared in rapid mixer granulator. (b) tartaric acid (Example 1)/ Maleic acid (Example 2)1 Fumaric acid (Example 3)/ Succinic acid (Example 4) was dissolved in purified water and butylated hydroxy toluene was dissolved in ethanol.

(c) Both solutions prepared in step (b) were added in the dry mixture prepared in step (a) to obtain granules;

(d) The granules prepared in step (c) were dried in fluidized bed dryer.

(e) The granules prepared in step (d) were mixed with lactose monohydrate and magnesium stearate.

(f) The above mixture prepared in step (e) was compressed to obtain tablet; and

(g) Tablets were coated with a film coating material.

Examples

Examples 5 to 8

stearate

Total weight (Un 150 150 150 150 coated)

Coating

14 Opadry Pink 4.5 4.5 4.5 4.5

Total weight (coated) 154.5 154.5 154.5 154.5

Process:

(a) dry mixture of solifenacin succinate, pregelatinized starch, lactose monohydrate and hydroxypropylmethyl cellulose was prepared in rapid mixer granulator.

(b) tartaric acid (Example 5)/ Maleic acid (Example 6)1 Fumaric acid (Example 1)1 Succinic acid (Example 8) was dissolved in purified water and butylated hydroxy toluene was dissolved in ethanol.

(c) Both solutions prepared in step (b) added in the dry mixture prepared in step (a) to obtain granules;

(d) The granules prepared in step (c) were dried in fluidized bed dryer.

(f) The above mixture prepared in step (e) was compressed to obtain tablet; and

(g) tablets were coated with a film coating material. Compositions of Example 5 to 7 were kept for forced degradation studies for 48 hours under the conditions of heat and moisture at 80°C. Forced degradation data of composition are summarized in table 1.

Stability indicating HPLC analytical method:

The measurement of N-oxide impurity of solifenacin was carried out using gradient- reverse phase HPLC with UV detection.

The method for determining the amount of N-oxide impurity in a solifenacin succinate tablet comprises the steps of:

a) dissolving the Solifenacin succinate tablet in mixture of water and acetonitrile to obtain a solution; b) injecting the sample solution into a HPLC column;

c) Measuring of the amounts of N-oxide impurity with a UV detector.

The Relative retention time of N-oxide impurity is about 1.09

Table 1 : Forced degradation data of compositions of examples 5 to 7

It was observed that compositions of present invention provided excellent stability for controlling N-oxide impurity in formulation.

Composition of Example 5 was kept for stability testing for 1 month under the conditions 40°C/75% RH. Stability data of composition are summarized in table 2.

Table 2 : Stability data of compositions of example 5

Examples

Examples 9 to 10

Process:

(b) tartaric acid was dissolved in purified water and butylated hydroxy toluene was dissolved in ethanol.

(c) Both solutions prepared in step (b) added in the dry mixture prepared in step (a) to obtain granules; (d) The granules prepared in step (c) were dried in fluidized bed dryer.

(f) The above mixture prepared in step (e) was compressed to obtain tablet; and

(g) tablets were coated with a film coating material.

Compositions of Examples 9 were packed in Alu-Alu blister and HDPE bottle for 6 month at 40°C/75% RH to determine impact of stabilizer to control the impurity (N- oxide) on the stability of the product. Results are summarized in Table 3.

Table 3 : Stability data of compositions of examples 9

It was observed that compositions of present invention provided excellent stability for controlling N-oxide impurity on stability in the composition.

When tested, it was observed that composition of present invention has been found more stable in comparison to marketed solifenacin compositions as herein described below:

Claims

We Claim:

1. A stable solid oral pharmaceutical composition comprising solifenacin; stabilizers selected from tartaric acid, fumaric acid, succinic acid and maleic acid; wherein said composition having a solifenacin N-oxide impurity in an amount of less than 0.1% under normal storage conditions.

2. The pharmaceutical composition of claim 1, wherein said solifenacin N-oxide impurity is present in an amount of less than 0.03%.

3. The pharmaceutical composition of claim 1, wherein solifenacin is in a substantially amorphous form.

4. The pharmaceutical composition of claim 1, wherein stabilizer is tartaric acid.

5. The pharmaceutical composition of claim 1, further comprises antioxidant which is selected from sodium hydrogen sulfite, tocopherol acetate, tocopherol, propyl gallate, Butyl hydroxy toluene and Butyl hydroxy anisole.

6. A stable solid oral pharmaceutical composition comprising of 5% to 12% w/w of solifenacin, 0.01% to 4% w/w of stabilizer selected from tartaric acid, succinic acid, maleic acid and fumaric acid, 0.01% to 4 % w/w of antioxidant, 0.01% to 5% w/w of binder, 1% to 25% w/w of disintegrant & 0.1% to 5% w/w of lubricant of total weight of the composition.

7. The composition of claim 6, wherein stabilizer is tartaric acid, antioxidant is butylated hydroxy toluene, binder is hydroxypropyl methyl cellulose, disintegrant is pregelatinized starch and lubricant is magnesium stearate.

8. The pharmaceutical composition of any of the claims above, wherein solifenacin is solifenacin succinate.

9. A process for preparing a stable solid oral pharmaceutical composition of solifenacin succinate comprising steps of:

(a) preparing a solution comprising a stabilizer selected from tartaric acid, maleic acid, fumaric acid & succinic acid , an antioxidant and solvent;

(b) granulating the mixture comprising solifenacin succinate, water soluble polymer & optionally other pharmaceutical excipient with solution prepared in step (a);

(c) optionally, drying the granules prepared in step (b);

10. A stable solid oral pharmaceutical composition comprising solifenacin succinate and process of its preparation as herein described with reference to the examples accompanying the specification.