阅读说明：本技术 使用包含内置沉降篮的转篮溶出装置的检测溶出方法 (Method for detecting dissolution using a rotary basket dissolution apparatus comprising a built-in sedimentation basket ) 是由 吴建设 范文源 崔波 李传虹 邵瑜 卞佳琳 李永灿 杜争鸣 于 2020-06-28 设计创作，主要内容包括：本发明涉及一种使用内置沉降篮的转篮溶出装置用于检测制剂溶出的方法。本发明中使用内置沉降篮与转篮结合的转篮溶出法能够显著降低溶出过程中粘性胶囊等固体制剂药物的溶出不均一、溶出平行性差的问题。该方法能够实现粘性的固体制剂药物(特别是胶囊)质量检测与控制,适用于溶出过程中容易变粘的胶囊制剂,尤其适用于微丸胶囊制剂的溶出度检测,特别地适用于在Pamiparib微丸胶囊制剂的溶出度检测。(The invention relates to a method for detecting dissolution of a preparation by using a rotary basket dissolution device with a built-in settling basket. The invention uses the basket dissolution method combining the built-in settling basket and the basket, which can obviously reduce the problems of nonuniform dissolution and poor dissolution parallelism of solid preparation medicines such as viscous capsules and the like in the dissolution process. The method can realize the quality detection and control of viscous solid preparation medicines (particularly capsules), is suitable for capsule preparations which are easy to become viscous in the dissolution process, is particularly suitable for the dissolution detection of pellet capsule preparations, and is particularly suitable for the dissolution detection of Pamiparib pellet capsule preparations.)

1. A method of dissolution testing using a basket dissolution apparatus comprising a built-in settling basket, wherein the basket dissolution apparatus comprising a built-in settling basket comprises a settling basket and a rotating basket, wherein the settling basket is disposed within the rotating basket, and wherein the solid dosage form is disposed within the settling basket, the method of use comprising the steps of:

1) dissolution:

a. placing the solid formulation into a dry settling basket;

b. placing the settling basket filled with the solid preparation into a rotating basket, and placing the rotating basket filled with the built-in settling basket into a container filled with a dissolving-out medium for dissolving out;

2) and (3) sample analysis:

a. sampling at the determined time point;

b. and (6) detecting.

2. The method according to claim 1, characterized in that the solid formulation is a tablet, capsule, pill, granule, pellet, liposome or microsphere, preferably a capsule or pellet, more preferably a pellet or pellet capsule, further preferably a viscous capsule or pellet, most preferably a pamicarb pellet capsule formulation.

3. The method as claimed in claim 1, wherein the settling basket is cylindrical and comprises a circular top, a circular bottom and a cylindrical outer basket body of the settling basket, the cylindrical outer basket body of the settling basket is formed by a spiral structure, a plurality of reinforcing ribs are fixed on the outer side of the spiral structure, the top and the bottom of the settling basket are respectively provided with a cross-linking structure, the bottom is fixedly connected with the edge of the settling basket body, one end of the top is fixed on a point on the edge of the settling basket body through a hinge so that the top can be opened and closed; the other end is provided with a buckle structure and is closed and locked in a buckle mode.

4. A spin basket dissolution apparatus comprising an internally disposed settling basket according to claim 3, wherein the helical structure and/or the ribs of the settling basket are made of a metallic or non-metallic material, preferably a stainless steel material, more preferably a stainless steel nickel plated material.

5. A spin basket dissolution apparatus according to claim 3 or 4 comprising a built-in settling basket having a length of 10mm to 30mm, preferably 15mm to 25mm, more preferably 18mm to 25mm, even more preferably 10mm, 12mm, 15mm, 18mm, 20mm, 22mm, 25mm, 28mm, 30 mm.

6. A spin basket dissolution apparatus comprising an internal settling basket according to claim 3, wherein the helical pitch of the helical structure is about 1-5mm, 2-4 mm, 3-5 mm, or 3-4mm, more preferably 3.0-3.5mm or 3.5-4.0 mm.

7. A spin basket dissolution apparatus comprising an internal settling basket according to claim 3, wherein the top or bottom circular diameter is about 7-15mm, more preferably 8-13mm, even more preferably 9 ± 0.5mm, 10 ± 0.5mm, 11 ± 0.5mm or 12 ± 0.5 mm.

8. A spin basket dissolution apparatus comprising an internally disposed sedimentation basket according to claim 3, wherein the spacing between the ribs is about 2 to 5mm, more preferably 3 to 4mm, still more preferably 3.0 to 3.5mm, and still more preferably 3.5 to 4.5 mm.

9. A spin basket dissolution apparatus according to claim 3 or 4 comprising an internally disposed settling basket, wherein the connections between the parts of the settling basket are preferably welded, preferably stainless steel corrosion resistant material, more preferably stainless steel material welded and nickel plated.

10. The method according to claim 1, characterized in that the dissolution medium is a physiological pH dissolution medium at pH1.0-pH8.0, preferably a dissolution medium of 0.1N HCl, a dissolution medium at pH4.5 or a dissolution medium at pH 6.8; more preferably 0.1N HCl.

11. The method of claim 1, wherein the method is capable of reducing test deviation values (e.g., RSD, SD) in a drug dissolution assay test method.

12. The method according to claim 1, characterized in that the method has a dissolution rate RSD% of less than 20% at the initial time point and a RSD% of less than 15% at other time points after the initial time point.

Technical Field

The present invention relates to a method for detecting dissolution of a preparation using a rotary basket dissolution apparatus comprising a built-in sedimentation basket.

Background

Dissolution is an important indicator of quality control of solid formulations, and for formulations in which dissolution is checked, the checking of disintegration time is generally not performed. The choice of dissolution device is generally based on the product formulation design and the dosage form characteristics in the in vitro testing system. The first method (basket method) and the second method (paddle method) in the Chinese pharmacopoeia and the United states pharmacopoeia are commonly used methods for detecting the dissolution rate of the preparation. For capsules, the first method (basket method) is preferred; since the capsule samples collapsed to the bottom of the basket, or adhered to the top of the basket, and easily floated on the liquid surface, the dissolution rate of the capsules was also measured by the paddle method plus a sedimentation basket method (second method). Two stirring speeds are often used in dissolution comparison studies using the first method: 75 and 100 revolutions per minute. Two stirring speeds are often used in dissolution comparison studies using the second method: 50 and 75 rpm. In the second method of paddle plus basket, a settling basket is generally used and since the rotating basket used in the basket method is itself provided with a cover and the rotating basket must be entirely immersed in a solvent for testing, it is not seen in the prior art that the settling basket is applied to the basket testing method.

When the capsule preparation is tested for dissolution, the relative standard deviation (for example, RSD%) of dissolution of the capsule becomes large due to floating of the capsule, sticking of the capsule shell or sticking of the drug particles as the raw material of the capsule during dissolution of the capsule, and development of the dissolution method becomes difficult.

WO2017/0322891 discloses compounds as inhibitors of poly (ADP-ribosyl) transferases (PARPs), and in particular discloses the sesquihydrate Pamiparib of a compound,

namely (R) -2-fluoro-10 a-methyl-7, 8,9,10,10a, 11-hexahydro-5, 6,7a, 11-tetraazacyclohepta [ def ] cyclopenta [ a ] fluoren-4 (5H) -one sesquihydrate. The compound is an inhibitor of poly Adenosine Diphosphate (ADP) ribose polymerase (PARP), has high selectivity to PARP-1/2, and can effectively inhibit proliferation of cell lines with BRCA1/2 mutation or other HR defects. Preclinical studies have shown that Pamiparib has significant advantages in safety and efficacy over olaparib and other PARP inhibitors (such as Veliparib) that enter clinical stage III of the us FDA: has stronger DNA capture activity; pamiprarib is about 16-fold more active than olaparib in experiments with an in vitro xenograft model of BRCA variation; and has better PARP1/2 selectivity, and rodents have good tolerance to Pamiparib and about 10 times of therapeutic window; in addition, the drug has no CYP inhibitory activity and shows strong combined drug activity and excellent pharmacokinetic properties: has excellent DMPK property and remarkable brain permeability.

Pamiparib has poor flowability, and is difficult to directly fill and produce in the preparation production process. Therefore, the inventor develops a Pamiparib capsule preparation, particularly a pellet capsule, successfully reduces the difficulty of the raw material medicine in the aspect of preparation, improves the fluidity and the stability of the product, and realizes large-scale commercial production.

However, pamiprarib is a drug with high viscosity, and the sticky drug can cause the phenomenon that the capsule floats and becomes sticky and sticks to a stirring rod during the dissolution analysis process, particularly during the in-vitro dissolution test process by using the traditional slurry method and basket method in pharmacopeia, so that the dissolution result is greatly changed, and the relative standard deviation (such as RSD%) of the dissolution result can not meet the requirements of the dissolution test of a sample. Therefore, there is a need for development of a specific dissolution method or apparatus suitable for viscous pharmaceutical preparations, which can accurately measure the dissolution rate of the viscous pharmaceutical preparation.

Disclosure of Invention

The rotary basket dissolution device containing the built-in sedimentation basket can overcome the defects that the dissolution result of a viscous medicine preparation, particularly a pellet capsule preparation, and more particularly a Pamiparib pellet capsule preparation has large change, and the relative standard deviation (such as RSD%) of the dissolution result cannot meet the requirements of a sample dissolution test, so that the dissolution rate of the viscous capsule preparation can be detected more accurately.

The invention also relates to a using method of the rotary basket dissolution device with the built-in settling basket.

Further, the invention relates to a method for applying a sedimentation basket in a first basket rotating method of a pellet capsule dissolution method.

In particular, the present invention relates to a dissolution process using a basket dissolution apparatus comprising a built-in settling basket, wherein a settling basket is placed inside the basket and the solid preparation is placed in the settling basket, the dissolution process comprising the steps of:

1) dissolution:

a. placing the solid formulation into a dry settling basket;

b. placing the settling basket filled with the solid preparation into a rotating basket, and placing the rotating basket filled with the built-in settling basket into a container filled with a dissolving-out medium for dissolving out;

2) and (3) sample analysis:

a. sampling at the determined time point;

b. and (6) detecting.

The solid preparation is tablets, capsules, pills, granules, pellets, liposomes or microspheres, preferably capsules or pellets, more preferably sticky capsules or pellets, and even more preferably pamicarb pellets or pamicarb capsules.

The sedimentation basket is cylindrical and comprises a circular top (A end), a circular bottom (B end) and a circular basket body on the periphery of the sedimentation basket cylinder, wherein the basket body on the periphery of the sedimentation basket cylinder is formed by a spiral structure, a plurality of basket bar reinforcing ribs are fixed on the outer side of the spiral structure, the top (A end) and the bottom (B end) of the sedimentation basket are respectively provided with a cross-linked structure ("#" shaped structure), the bottom (B end) is fixedly connected to the edge of the sedimentation basket body, and one end of the top (A end) is fixed to one point on the edge of the sedimentation basket body through a hinge so that the top can be opened and closed; the other end is provided with a buckle structure and is closed and locked in a buckle mode.

The spiral structure and/or the reinforcing ribs of the settling basket are made of metal or nonmetal materials, preferably stainless steel materials, and more preferably stainless steel nickel-plated materials.

The length of the settling basket is 10mm-30mm, preferably 15mm-25mm, more preferably 18mm-25mm, further preferably 10mm, 12mm, 15mm, 18mm, 20mm, 22mm, 25mm, 28mm, 30 mm.

The helical pitch of the helical structure is about 1-5mm, 2-4 mm, 3-5 mm, or 3-4mm, more preferably 3.0-3.5mm or 3.5-4.0 mm.

The top or bottom circular diameter is about 7-15mm, more preferably 8-13mm, and even more preferably 9 + -0.5 mm, 10 + -0.5 mm, 11 + -0.5 mm or 12 + -0.5 mm.

The spacing between the reinforcing ribs of each basket bar is about 2-5mm, more preferably 3-4mm, further preferably 3.0-3.5mm and 3.5-4.5 mm.

The connection mode among each part of the settling basket is preferably welding, the material is preferably stainless steel material, preferably stainless steel corrosion-resistant material, and more preferably the stainless steel material is welded and then plated with nickel.

The dissolution medium of the method is pH dissolution medium of pH1.0-pH8.0 physiological conditions, preferably 0.1N HCl dissolution medium, pH4.5 dissolution medium or pH6.8 dissolution medium; more preferably 0.1N HCl.

The method can reduce the RSD% value in a drug dissolution analysis test method.

Preferably, the method has a dissolution rate RSD% of less than 20% at the starting time point and a RSD% of less than 15% at other time points after the starting time point.

The basket structure is shown in figures 1 and 2 with a settling basket placed inside.

The dissolution method provided by the invention can be applied to any preparation with nonuniform dissolution and poor dissolution parallelism in the dissolution process; the solid preparation is preferably tablets, capsules, pills, granules, pellets, liposomes, microspheres, further preferably pellets and capsules, including but not limited to pamicarb pellets and pamicarb capsule preparations. The Pamiparib capsule preparation can be a pellet capsule preparation, a granule capsule preparation or a powder capsule preparation.

Further, the dissolution method according to the present invention is:

1) dissolution:

a. placing the solid formulation into a dry settling basket;

b. placing the settling basket filled with the solid preparation into a rotary basket, placing the rotary basket with the settling basket inside into a dissolving cup filled with a specific volume of dissolving medium preheated to the range of 37 +/-0.5 ℃ according to the conventional dissolving requirements in the field for dissolving, and sampling at a specified sampling time point (for example, 10 minutes, 15 minutes, 20 minutes, 30 minutes and/or 45 minutes).

2) And (3) sample analysis:

a. sampling the specified sampling time point to dissolve out the sample;

b. analytical determination was performed using UV or HPLC.

The settling basket is preferably the aforementioned 18mm or 25mm length settling basket. The dissolution medium may be selected from 0.1N HCl in water, pH4.5 in water or pH6.8 in water. The volume of dissolution medium is preferably 900 mL.

The dissolution method provided by the invention can be applied to any preparation with nonuniform dissolution and poor dissolution parallelism in the dissolution process; the solid preparation is preferably tablets, capsules, pills, granules, pellets, liposomes, microspheres, further preferably pellets and capsules, including but not limited to pamicarb pellets and pamicarb capsule preparations. The Pamiparib capsule preparation can be a pellet capsule preparation, a granule capsule preparation or a powder capsule preparation.

Preferably, the basket rotation speed of the dissolution process is 50-250 rpm, preferably 50-100 rpm, preferably 75-100 rpm, more preferably 75 or 100 rpm.

Preferably, the dissolution media for the dissolution method are 0.1N HCl in water, pH4.5 in water and pH6.8 in water, preferably 0.1N HCl in water.

The dissolution method can reduce the RSD% value in the analysis test method of the drug dissolution rate, and the dissolution rate RSD% of the dissolution method at the initial time point is less than 20%, and the RSD% of the dissolution method at other time points except the initial time point is less than 15%.

By way of example, the basket dissolution with internal settling basket of the present invention can be used in pamicarb formulations, such as pellet compositions. The Pamiparib preparation is a pellet composition, and specifically comprises the following components: pellets comprising (1) a pellet core and optionally an additional excipient; (2) a drug-containing layer and (3) an optional protective layer; the drug-containing layer comprises (a) an active ingredient and (b) a binder; when the composition comprises a protective layer, the protective layer comprises (c) a coating material; the active ingredient is (R) -2-fluoro-10 a-methyl-7, 8,9,10,10a, 11-hexahydro-5, 6,7a, 11-tetraazacyclohepta [ def ] cyclopenta [ a ] fluorene-4 (5H) -ketone, pharmaceutically acceptable salt and hydrate thereof.

In the above pellet compositions, the optional additional excipients include, but are not limited to, fillers, lubricants and other conventionally used excipients. Preferably the additional excipient comprises one or more of a filler, a lubricant, more preferably the additional excipient comprises a lubricant.

Optionally, the additional excipient is admixed with a composition comprising (1) a pellet core; (2) mixing the pellets of the drug-containing layer and (3) the optional protective layer.

In the pellet composition, the pellet core is a blank pellet core and is selected from one or more of a sucrose pellet core, a microcrystalline cellulose pellet core and a starch pellet core.

In the pellet composition, the pellet core accounts for 50-90 wt%, preferably 60-85 wt% (w/w) of the total weight of the pellet composition.

In the above pellet composition, the active ingredient is preferably (R) -2-fluoro-10 a-methyl-7, 8,9,10,10a, 11-hexahydro-5, 6,7a, 11-tetraazacyclohepta [ def ] cyclopenta [ a ] fluoren-4 (5H) -one in the a-L crystal form or (R) -2-fluoro-10 a-methyl-7, 8,9,10,10a, 11-hexahydro-5, 6,7a, 11-tetraazacyclohepta [ def ] cyclopenta [ a ] fluoren-4 (5H) -one in a hydrate form.

Preferably, the active ingredient is the C crystal form of (R) -2-fluoro-10 a-methyl-7, 8,9,10,10a, 11-hexahydro-5, 6,7a, 11-tetraazacyclohepta [ def ] cyclopenta [ a ] fluoren-4 (5H) -one.

The A-L crystal form can be prepared by referring to WO2017/032289A 1.

Preferably, the active ingredient is a sesquihydrate of (R) -2-fluoro-10 a-methyl-7, 8,9,10,10a, 11-hexahydro-5, 6,7a, 11-tetraazacyclohepta [ def ] cyclopenta [ a ] fluoren-4 (5H) -one having the following structure:

preferably, D of said active ingredient₉₀Less than 100 μm, preferably D₉₀Less than 50 μm, more preferably D of the active ingredient₉₀Less than 30 μm. .

Preferably, the active ingredient is 5-50%, preferably 10-25%, and more preferably 10-20% (w/w) by weight of the total pellet composition.

Preferably, the active ingredient is (R) -2-fluoro-10 a-methyl-7, 8,9,10,10a, 11-hexahydro-5, 6,7a, 11-tetraazacyclohepta [ def [ ]]Cyclopenta [ a ]]C crystal form of fluorene-4 (5H) -ketone and particle size D₉₀Less than 30 μm, the active ingredient is present in an amount of 10% to 25% (w/w), more preferably 10% to 20%, by weight of the total pellet composition.

Preferably, the active ingredient is (R) -2-fluoro-10 a-methyl-7, 8,9,10,10a, 11-hexahydro-5, 6,7a, 11-tetraazacyclohepta [ def [ ]]Cyclopenta [ a ]]Sesquihydrate of fluorene-4 (5H) -one, particle size D₉₀Less than 30 μm, the active ingredient is present in an amount of 10% to 25% (w/w), more preferably 10% to 20%, by weight of the total pellet composition.

In the pellet composition, the binder includes, but is not limited to, one or more of carbomer, sodium carboxymethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and povidone.

In the pellet composition, the binder accounts for 1-20 wt%, preferably 1-10 wt%, more preferably 3-8 wt%, and most preferably 3-6 wt% (w/w) of the total weight of the pellet composition.

Preferably, the binder is selected from hypromellose, hypromellose sodium and povidone.

More preferably, the binder is hypromellose and hypromellose sodium in an amount of 3-8% (w/w) based on the total weight of the pellet composition.

In the pellet composition, the coating material includes but is not limited to one or more of carbomer, sodium carboxymethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose and povidone.

In the pellet composition, the weight percentage of the coating material to the total weight of the pellet composition is 1-25%, preferably 1-10%, more preferably 1.5-8%, and most preferably 3-6% (w/w).

Preferably, the coating material is selected from hypromellose and hypromellose sodium.

More preferably, the coating material is hydroxypropyl methylcellulose and hydroxypropyl methylcellulose sodium which account for 1.5-8% (w/w) of the total weight of the pellet composition.

In the pellet composition, the lubricant includes, but is not limited to, one or more of calcium stearate, magnesium stearate, zinc stearate, stearic acid, sodium stearyl fumarate and talc.

In the pellet composition, the lubricant accounts for 0.1-5.0 wt%, preferably 0.1-2 wt% of the total weight of the pellet composition. More preferably 0.5% to 1.5% (w/w).

After the Pamiparib is prepared into the pellets, a certain lubricant, particularly talcum powder, is mixed into the pellets, so that the electrostatic effect of the pellets can be effectively reduced, and the mass commercial production of the preparation becomes possible. Thus, preferably, the lubricant is selected from talc.

Preferably, the lubricant is selected from 0.1-2 wt% of talcum powder based on the total weight of the pellet composition.

By way of further example, the pamiprarib formulation may be a pellet composition provided in the form comprising: (1) an active ingredient which is (R) -2-fluoro-10 a-methyl-7, 8,9,10,10a, 11-hexahydro-5, 6,7a, 11-tetraazacyclohepta [ def ] cyclopenta [ a ] fluoren-4 (5H) -one, a pharmaceutically acceptable salt and a hydrate thereof; (2) a pellet core; (3) a binder; (4) optionally a coating material; and (5) optionally additional excipients.

In some embodiments, the present invention relates to a PARP inhibitor pellet composition comprising: (1) an active ingredient which is (R) -2-fluoro-10 a-methyl-7, 8,9,10,10a, 11-hexahydro-5, 6,7a, 11-tetraazacyclohepta [ def ] cyclopenta [ a ] fluoren-4 (5H) -one, a pharmaceutically acceptable salt thereof and a hydrate thereof; (2) a pellet core; (3) a binder; and (4) optionally additional excipients.

In other embodiments, the present invention relates to a PARP inhibitor pellet composition comprising: (1) an active ingredient which is (R) -2-fluoro-10 a-methyl-7, 8,9,10,10a, 11-hexahydro-5, 6,7a, 11-tetraazacyclohepta [ def ] cyclopenta [ a ] fluoren-4 (5H) -one, a pharmaceutically acceptable salt thereof and a hydrate thereof; (2) a pellet core; (3) a binder; (4) coating materials; and (5) optionally additional excipients.

By way of further example, the pamiprarib pellet composition is prepared as follows:

a method of preparing a pellet composition, the method comprising the steps of:

1) dispersing the active ingredient in the adhesive solution to prepare a drug-containing suspension;

2) spraying the drug-containing suspension liquid obtained in the step 1) on the pellet core surface to form a drug-containing layer, and preparing a drug-loaded pellet;

3) preparing a coating material solution, spraying the coating material solution on the surface of the drug-loaded pellets to be used as a protective layer, and preparing protective layer pellets, wherein the step is optionally executed;

4) mixing the pellets obtained in the step 2) or the step 3) with an external excipient to prepare a total mixed pellet, wherein the step is optionally executed.

In some embodiments, the present invention relates to a method of preparing a pellet composition, the method comprising the steps of:

1) dispersing the active ingredient in the adhesive solution to prepare a drug-containing suspension;

2) spraying the drug-containing suspension liquid obtained in the step 1) on the pellet core surface to form a drug-containing layer, and preparing a drug-loaded pellet;

3) preparing a coating material solution, spraying the coating material solution on the surface of the drug-loaded pellets to be used as a protective layer, and preparing the protective layer pellets to obtain the pellet composition.

In some embodiments, the present invention relates to a method of preparing a pellet composition, the method comprising the steps of:

1) dispersing the active ingredient in the adhesive solution to prepare a drug-containing suspension;

2) spraying the drug-containing suspension liquid obtained in the step 1) on the pellet core surface to form a drug-containing layer, and preparing a drug-loaded pellet;

3) mixing the pellets obtained in the step 2) with an external excipient to prepare total mixed pellets, namely the pellet composition.

In some embodiments, the present invention relates to a method of preparing a pellet composition, the method comprising the steps of:

1) dispersing the active ingredient in the adhesive solution to prepare a drug-containing suspension;

2) spraying the drug-containing suspension liquid obtained in the step 1) on the pellet core surface to form a drug-containing layer, and preparing a drug-loaded pellet;

3) preparing a coating material solution, and spraying the coating material solution on the surface of the drug-loaded pellet as a protective layer to prepare a protective layer pellet;

4) mixing the pellets obtained in the step 3) with an external excipient to prepare total mixed pellets, thus obtaining the pellet composition.

The method of the present invention further comprises encapsulating the total pellet blend into a capsule.

The capsule includes a capsule shell. The capsule shell is selected from gelatin hollow capsule shell and hypromellose hollow capsule shell, preferably gelatin hollow capsule shell. The capsules with different specifications can be filled according to the content of the raw material medicament in the pellets and the weight of the pellets, and the specifications comprise but are not limited to 5mg, 10mg, 20mg, 30mg, 40mg, 50mg, 60mg, 70mg, 80mg and 100mg of active ingredients contained in each capsule by the weight of (R) -2-fluoro-10 a-methyl-7, 8,9,10,10a, 11-hexahydro-5, 6,7a, 11-tetraazacyclohepta [ def ] cyclopenta [ a ] fluorene-4 (5H) -ketone.

Pamiprarib belongs to the hypo-lytic hypertonic class (BCS class 2) of drugs. A similarity factor f2 and a difference factor f1 should be used in performing the dissolution profile similarity comparison. The development of the elution method is critical to satisfying the requirement of the f2 factor method.

f₁＝{[∑_t＝1 ⁿ|R_t-T_t|]/[∑_t＝1 ⁿR_t]}·100

f₂＝50·log{[1+(1/n)∑_t＝1 ⁿ(R_t-T_t)²]^-0.5·100}

1. When the similarity factor f2 is more than or equal to 50 and the difference factor f1 is less than or equal to 15, the two dissolution curves are considered to be similar.

2. The tested preparation and the reference preparation only have one sampling point with the dissolution amount of more than 85 percent, and at least 2 sampling points with the dissolution amount of less than 85 percent.

3. The amount of elution at the first sampling time point (e.g., 10 minutes or 15 minutes) should not exceed 20% relative to the standard deviation (RSD%), and the amount of elution at the remaining sampling time points should not exceed 10% relative to the standard deviation (RSD%).

4. When the elution amount of the test preparation and the reference preparation is not less than 85% within 15 minutes, the comparison of f2 is not necessary.

The rotary basket dissolution method combining the sedimentation basket and the rotary basket can obviously reduce the relative standard deviation RSD in the dissolution test of the pharmaceutical preparation with poor dissolution parallelism in the dissolution process, and can ensure that the developed detection method can effectively carry out quality detection on the pharmaceutical preparation.

Drawings

The following figures illustrate the invention, but the invention is not limited thereto.

FIG. 1 is a perspective view of a rotary basket dissolution apparatus incorporating a built-in settling basket.

Figure 2. six-sided view of a rotary basket dissolution apparatus incorporating a built-in settling basket.

Figure 3 six side views of an internal settling basket in a closed state.

FIG. 4.18mm long settling basket, A being the top of the basket and B being the bottom of the basket

FIG. 5.25mm long settling basket, A being the top of the basket and B being the bottom of the basket

FIG. 6A. A spin basket dissolution apparatus comprising a built-in settling basket (open state), and

figure 6b. internal settling basket in open state.

Detailed Description

The following examples may assist those skilled in the art in a more complete understanding of the present invention, but are not intended to limit the invention in any way.

EXAMPLE 1 spin basket dissolution apparatus with built-in settling basket

A basket dissolution apparatus with a built-in settling basket, the structure of which is shown in figures 1 and 2, the settling basket is arranged in the rotating basket. Sedimentation basket structure as shown in fig. 4, the sedimentation basket is cylindrical and is set to 18mm length specification according to capsule length (or height) specification. The 18mm settling basket is approximately 18mm in length (or height) and approximately 10mm in diameter circular at the top (a) or bottom (B).

The metal helical structure forms a peripheral basket body of the cylindrical body of the settling basket, and the helical pitch of the helical structure is about 3.0-3.5 mm. A plurality of basket reinforcing ribs are fixed on the outer side of the spiral structure, and the space between the 18mm settling basket reinforcing ribs is about 3.0-3.5 mm. The spiral structure is connected with the reinforcing ribs in a welding mode to form a firm settling basket body structure.

The top (A end) and the bottom (B end) of the settling basket are respectively of a cross-linked structure, and the distance between the cross-linked structures of the settling baskets with the length of 18mm is about 3.0-3.5 mm. The bottom (B end) is welded at the bottom of the sedimentation basket body structure. As shown in fig. 6A and 6B, the top (a-end) of the settling basket is fixed at one end by a hinge to a fixed point on the top edge of the basket body of the settling basket so that the top can be opened and closed. The top (A end) of the settling basket is provided with a buckle structure and is closed and locked in a buckle mode.

The settling basket is made of stainless steel material, and the stainless steel is subjected to nickel plating treatment after welding.

EXAMPLE 2 spin basket dissolution apparatus with built-in settling basket

A basket dissolution apparatus with a built-in settling basket, the structure of which is shown in figures 1 and 2, the settling basket is arranged in the rotating basket. Sedimentation basket structure as shown in fig. 5, the sedimentation basket is cylindrical and is set to 25mm length specification according to capsule length (or height) specification. The 25mm settling basket is about 25-26mm in length (or height) and about 12mm in diameter circular at the top (a) or bottom (B).

The metal helical structure forms a peripheral basket body of the cylindrical body of the settling basket, and the helical pitch of the helical structure is about 3.0-3.5 mm. A plurality of basket reinforcing ribs are fixed on the outer side of the spiral structure, and the distance between the 25mm settling basket reinforcing ribs is about 3.5-4.0 mm. The spiral structure is connected with the reinforcing ribs in a welding mode to form a firm settling basket body structure.

The top (A end) and the bottom (B end) of the settling basket are respectively of a cross-linked structure, and the distance between the cross-linked structures of the settling basket with the thickness of 25mm is about 3.5-4.0 mm. The bottom (B end) is welded at the bottom of the sedimentation basket body structure. As shown in fig. 6A and 6B, one end of the top (end a) of the settling basket is fixed to a fixing point on the top edge of the basket body of the settling basket by a hinge as a fixing point so that the top can be opened and closed. The top (A end) of the settling basket is provided with a buckle structure and can be closed and locked in a buckle mode.

The settling basket is made of stainless steel material, and the stainless steel is subjected to nickel plating treatment after welding.

Example 3 rotating basket dissolution assay with built-in settling basket for Pamiparib pellet Capsule formulation

1) Dissolution:

a. the pamicarb pellet capsule formulation (size: 20 mg) was placed in a dry 18m long settling basket (fig. 4);

b. placing the settling basket filled with the Pamiparib pellet capsule preparation (specification: 20 mg) into a rotary basket, preheating a dissolution medium (0.1 mol/L hydrochloric acid, 900mL) to be within a range of 37 +/-0.5 ℃, placing the rotary basket with the settling basket ready to be placed into a dissolution cup filled with the dissolution medium with a specific volume preheated to be within the range of 37 +/-0.5 ℃ according to the conventional dissolution requirements in the field for dissolution, wherein the rotating speed is 75 revolutions per minute and 100 revolutions per minute, and sampling at specified sampling time points (10 minutes, 15 minutes, 20 minutes, 30 minutes and 45 minutes).

2) And (4) analyzing the sample, namely sampling the dissolved sample at the specified sampling time point, and performing analysis determination by using UV or HPLC.

TABLE 1 rotating basket dissolution assay of Pamiparib pellet Capsule formulation (specification: 20 mg) built-in settling basket

EXAMPLE 4 Pamiparib pellet Capsule formulation (size: 20 mg) screening of dissolution media for basket-built in basket-spin dissolution

1) Dissolution:

a. the pamicarb pellet capsule formulation (size: 20 mg) was placed in a dry 18m long settling basket (fig. 4);

b. placing the settling basket filled with the Pamiparib pellet capsule preparation (specification: 20 mg) into a rotating basket, respectively preheating a dissolving medium (0.1 mol/L hydrochloric acid, 900 mL; water with pH4.5, 900 mL; water with pH6.8, 900mL) to be within the range of 37 +/-0.5 ℃, placing the rotating basket with the settling basket inside into a dissolving cup filled with a specific volume of dissolving medium preheated to the range of 37 +/-0.5 ℃ according to the conventional dissolving requirements in the field for dissolving, wherein the rotating speed is 75 revolutions per minute and 100 revolutions per minute, and sampling at specified sampling time points (10 minutes, 15 minutes, 20 minutes, 30 minutes and 45 minutes).

2) And (4) analyzing the sample, namely sampling the dissolved sample at the specified sampling time point, and performing analysis determination by using UV or HPLC.

The dissolution rates of 3 batches of pamipiarib pellet capsule formulations (specification: 20 mg) in a medium of 0.1N HCl in water, ph4.5 in water and ph6.8 in water were compared.

TABLE 2 dissolution ratio of PAMIPARIB pellet capsule formulation (specification: 20 mg) in 0.1N HCl and pH4.5 media

Comparative example 1 dissolution assay of 20mg pamicarb pellet capsule formulation using the conventional basket method

1) Dissolution: the Pamiparib pellet capsule preparation (specification: 20 mg) is placed into a drying rotary basket, a dissolution medium (0.1 mol/L hydrochloric acid, 900mL) is preheated to the temperature of 37 +/-0.5 ℃, the rotary basket prepared with the Pamiparib pellet capsule preparation (specification: 20 mg) is placed into a dissolution cup containing the dissolution medium with a specific volume preheated to the temperature of 37 +/-0.5 ℃ according to the conventional dissolution requirement in the field for dissolution, the rotating speed is 75 and 100 revolutions/minute, and sampling is carried out at the specified sampling time point.

2) Sample analysis, dissolution samples were taken at the specified sampling time points (10 min, 15 min, 20 min, 30 min, 45 min) and analyzed using UV or HPLC.

TABLE 3 dissolution assay (0.1 mol/L hydrochloric acid) for Pamiparib pellet capsule formulation (size: 20 mg) by the general basket method

The relative standard deviation (RSD%) of dissolution at 10 minutes of PAMIPARIB pellet capsules (specification: 20 mg) at 75 r/min and 100 r/min using basket method is 25% and 24%, respectively, which does not meet the requirements of f2 factor method under which dissolution comparison can not be performed using f2 factor method.

Comparative example 2 dissolution assay of Pamiparib pellet Capsule formulation (size: 20 mg) Using the sedimentation basket Paddle method

1) Dissolution: the Pamiparib pellet capsule preparation (specification: 20 mg) is put into a dry Sotax settling basket and a settling basket shown in figure 4, when a dissolving medium (0.1 mol/L hydrochloric acid, 900mL) is preheated to be within the range of 37 +/-0.5 ℃, the prepared settling basket is put into a dissolving cup containing a specific volume of the dissolving medium preheated to be within the range of 37 +/-0.5 ℃ according to the conventional dissolving requirements in the field for paddle dissolving, the rotating speed is 50 and 75 revolutions per minute, and sampling is carried out at specified sampling time points (10 minutes, 15 minutes, 20 minutes, 30 minutes and 45 minutes).

2) And (4) analyzing the sample, namely sampling the dissolved sample at the specified sampling time point, and performing analysis determination by using UV or HPLC.

TABLE 4 sedimentation basket paddle method dissolution assay (0.1 mol/L hydrochloric acid) for Pamiparib pellet capsule formulation (size: 20 mg)

The relative standard deviation (RSD%) of PAMIPARIB pellet capsules (specification: 20 mg) dissolved in a paddle plus a settling basket (50 and 75 rpm) at 10 minutes and 15 minutes does not meet the requirements of the f2 factor method, and the dissolution comparison is not suitable under the method.

As can be seen from the comparison of example 3 with comparative examples 1 and 2, the pamipiarib pellet capsule (size: 20 mg) in comparative example 1 has 25% and 24% of the relative standard deviation (RSD%) of dissolution at 10 minutes at 75rpm and 100rpm using the basket method, respectively, which does not meet the requirement of the f2 factor method, under which the dissolution comparison cannot be performed using the f2 factor method. In comparative example 2, the relative standard deviation (RSD%) of the dissolution of PAMIPARIB pellet capsules (size: 20 mg) in a paddle plus 18mm settling basket (50 and 75 rpm) at 10 minutes and 15 minutes also did not meet the requirements of the f2 factor method under which dissolution comparisons were not appropriate. In example 3, the relative standard deviation (RSD%) of dissolution was satisfactory at each time point, but 100rpm was significantly lower than 75rpm, with better reproducibility and a more ordered dissolution profile at 100 rpm. As can be seen from the screening of the dissolution media in example 4, the dissolution media can be 0.1N HCl, pH4.5 and pH6.8, with 0.1N HCl being most preferred as the simulated dissolution media for gastric fluid.

The use of a basket in combination with a settling basket in the present invention can significantly reduce the relative standard deviation (RSD%) in dissolution testing of viscous drug capsules, enabling the development of a test method effective for quality testing of such formulations.