A composition of quetiapine fumarate and a method for preparing the same

Abstract

This invention provides a quetiapine fumarate tablet composition and its preparation method. The composition contains the following components: quetiapine fumarate-hydroxypropyl-β-cyclodextrin co-treated product, povidone, calcium hydrogen phosphate, microcrystalline cellulose, sodium carboxymethyl starch, lactose monohydrate, magnesium stearate, and omeprazole. This invention also provides a method for processing a large-particle-size, highly fluid, highly soluble, and stable active pharmaceutical ingredient (API). This involves adding the API to a hydroxypropyl-β-cyclodextrin solution, homogenizing the resulting suspension, and spray-drying to prepare the quetiapine fumarate-hydroxypropyl-β-cyclodextrin co-treated product. The resulting intermediate powder obtained by wet granulation of the above-mentioned API-containing product exhibits superior flowability, smaller relative standard deviation of content uniformity, and a faster tableting rate after compression compared to tablets prepared solely from large-particle-size APIs, which is highly beneficial for industrial-scale production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical manufacturing, and specifically relates to the formulation process of quetiapine fumarate tablets. Background Technology

[0002] Quetiapine (trade name: Stroga), developed by AstraZeneca in the UK, was approved by the US FDA on September 26, 1997. Clinically, it is used to treat mental disorders including schizophrenia, bipolar disorder, generalized anxiety disorder, and adjunctive major depressive disorder. Quetiapine is a representative of second-generation antipsychotics, favored in clinical practice because it is effective for both positive and negative symptoms in schizophrenia patients, improves cognitive function, and has mild adverse reactions. Currently, quetiapine is a first-line treatment for schizophrenia and bipolar disorder.

[0003] Quetiapine fumarate is a white or off-white powder, odorless and tasteless, slightly soluble in water, methanol, and anhydrous ethanol. Most quetiapine fumarate formulations are tablets (including immediate-release and sustained-release tablets). Immediate-release tablets are available in strengths of 25mg, 50mg, 100mg, 150mg, 200mg, and 300mg. For low-dose formulations, the 2020 edition of the Chinese Pharmacopoeia explicitly stipulates that drug formulations with a single-dose label not exceeding 25mg or an active ingredient content not exceeding 25% require content uniformity testing. This necessitates that the intermediate powder of this specification must have good flowability to ensure that content uniformity meets requirements during material mixing and tableting.

[0004] Quetiapine fumarate is a BCS class II drug, poorly soluble and highly osmotic. In preparing the aforementioned tablets, the active pharmaceutical ingredient (API) is generally required to be further pulverized. This not only wastes manpower and resources, but also results in the API exhibiting disadvantages such as high static electricity, powder agglomeration, and poor flowability.

[0005] In summary, it is of great significance to prepare a drug substance or drug substance processing product that does not require pulverization, has good flowability and good solubility.

[0006] This invention utilizes the hydrophobic cavity of hydroxypropyl-β-cyclodextrin to increase the solubility and improve the stability of poorly soluble drugs, and then uses efficient and energy-saving spray technology to obtain a co-processed product of large-particle-size active pharmaceutical ingredients with good flowability and solubility, which is conducive to production and use.

[0007] Terminology explanation: D90 represents the diameter of the particles at 90% volume in the cumulative particle size distribution curve. Summary of the Invention

[0008] This invention provides a method for preparing active pharmaceutical ingredients with large particle size, good flowability, good solubility, and good stability, and uses the co-processed product to prepare tablets. The intermediate powder and the final product all meet the requirements for key quality attributes, providing a good solution to the problem of commercial production of poorly soluble and low-dose quetiapine fumarate tablets.

[0009] According to some aspects of the present invention, a quetiapine fumarate composition is provided, the quetiapine fumarate composition comprising the following components: quetiapine fumarate-hydroxypropyl-β-cyclodextrin co-treated product, povidone, dicalcium phosphate, microcrystalline cellulose, sodium carboxymethyl starch, lactose monohydrate, magnesium stearate, and omeprazole. Opadryl is a gastrointestinal coating material.

[0010] According to some aspects of the present invention, a quetiapine fumarate composition is provided, the composition comprising 56% to 85% quetiapine fumarate-hydroxypropyl-β-cyclodextrin co-treated product, 3% to 7% povidone, 2% to 5% dicalcium phosphate, 2% to 10% microcrystalline cellulose, 3% to 7% sodium carboxymethyl starch, 2% to 12% lactose monohydrate, 1% magnesium stearate, a coating weight gain of 2% to 4% of the aforementioned weight, and using the aforementioned Opadry.

[0011] According to some aspects of the present invention, a quetiapine fumarate-hydroxypropyl-β-cyclodextrin co-treated product is provided, the quetiapine fumarate-hydroxypropyl-β-cyclodextrin co-treated product comprising 33% to 50% quetiapine fumarate and 50% to 67% hydroxypropyl-β-cyclodextrin.

[0012] According to some aspects of the present invention, a method for preparing a quetiapine fumarate-hydroxypropyl-β-cyclodextrin co-treated product is provided, wherein the steps of the preparation method are as follows:

[0013] In a preparation container, after adding purified water, hydroxypropyl-β-cyclodextrin is added first and stirred to dissolve. Then, quetiapine fumarate raw material is added, with a feeding ratio of hydroxypropyl-β-cyclodextrin to quetiapine fumarate raw material of 1:1 to 2:1. Stirring is started to obtain a suspension of hydroxypropyl-β-cyclodextrin and raw material. The suspension is then homogenized using a homogenizer, and the particle size range D90 needs to be controlled to be 350 to 400 μm. Finally, spray drying is performed to obtain the co-treated product of quetiapine fumarate and hydroxypropyl-β-cyclodextrin.

[0014] According to some aspects of the present invention, a method for preparing quetiapine fumarate tablets is provided, wherein the above-mentioned quetiapine fumarate-hydroxypropyl-β-cyclodextrin co-treated product, povidone, dicalcium phosphate, microcrystalline cellulose, sodium carboxymethyl starch, and lactose monohydrate are premixed, wet granulated, wet granulated, and dried in an oven after being dry granulated, and then magnesium stearate is added for total mixing, tableting, and coating.

[0015] According to some aspects of the present invention, a method for preparing quetiapine fumarate tablets is provided, characterized in that the material ratio used in the above method is as follows:

[0016] The above-mentioned quetiapine-hydroxypropyl-β-cyclodextrin co-treated product contains 56%–85%, povidone 3%–7%, dicalcium phosphate 2%–5%, microcrystalline cellulose 2%–10%, sodium carboxymethyl starch 3%–7%, lactose monohydrate 2%–12%, magnesium stearate 1%, and the weight gain of the coated tablets is 2%–4%.

[0017] One method for preparing quetiapine fumarate tablets according to the present invention is as follows:

[0018] The above-mentioned components, comprising 56%–85% quetiapine fumarate-hydroxypropyl-β-cyclodextrin co-processed compound, 3%–7% povidone, 2%–5% dicalcium phosphate, 2%–10% microcrystalline cellulose, 3%–7% sodium carboxymethyl starch, and 2%–12% lactose monohydrate, were premixed, wet-granulated, and wet-sizingd in a wet granulator. After wet granulation, the granules were dried in an oven at 60±5℃. After dry granulation, 1% magnesium stearate was added for total mixing, tableting, and coating with Opadry at a weight gain of 2%–4%.

[0019] According to some aspects of the present invention, a quetiapine fumarate tablet is provided, which is prepared using any of the methods described above.

[0020] This invention provides a quetiapine fumarate tablet composition and its preparation method. The composition contains the following components: quetiapine fumarate-hydroxypropyl-β-cyclodextrin co-treated product, povidone, calcium hydrogen phosphate, microcrystalline cellulose, sodium carboxymethyl starch, lactose monohydrate, magnesium stearate, and omeprazole. This invention also provides a method for processing a large-particle-size, highly fluid, highly soluble, and stable active pharmaceutical ingredient (API). This involves adding the API to a hydroxypropyl-β-cyclodextrin solution, homogenizing the resulting suspension, and spray-drying to prepare the quetiapine fumarate-hydroxypropyl-β-cyclodextrin co-treated product. The resulting intermediate powder obtained by wet granulation of the above-mentioned API-containing treated product exhibits superior flowability, smaller relative standard deviation of content uniformity, and a faster tableting rate after compression compared to tablets prepared solely from large-particle-size APIs, which is highly beneficial for industrial-scale production. Attached Figure Description

[0021] Figure 1 Particle size distribution of the quetiapine fumarate-hydroxypropyl-β-cyclodextrin co-treated product prepared in Example 1 of this invention;

[0022] Figure 2 Microscopic images of quetiapine fumarate (untreated) in Example 2 of this invention;

[0023] Figure 3 Microscopic images of the quetiapine fumarate-hydroxypropyl-β-cyclodextrin co-treated product in Example 2 of this invention;

[0024] Figure 4 Dissolution curves of the tablets prepared in Example 6 of this invention;

[0025] Figure 5 The stability of the tablets prepared in Example 7 of this invention is represented by the HPLC chromatogram (0 days).

[0026] Figure 6 The stability of the tablets prepared in Example 7 of this invention is represented by the HPLC chromatogram (30 days).

[0027] Figure 7 The sampling points in Embodiment 3 of the present invention;

[0028] Figure 8 The sampling points in Embodiment 4 of the present invention. Detailed Implementation

[0029] The following embodiments are for further illustration of some preferred embodiments of the present invention and are not all embodiments. Other embodiments based on the present invention made by those skilled in the art without inventive effort are all within the scope of protection of the present invention. The present invention will be further described below with reference to the accompanying drawings.

[0030] Example 1:

[0031] prescription:

[0032]

[0033]

[0034] In a 30L preparation container, after adding purified water at 25℃, hydroxypropyl-β-cyclodextrin was added first. The stirring speed was set to 10-15 rpm, and the mixture was stirred until dissolved. Then, quetiapine fumarate raw material was added. The mixture was stirred for 30-45 minutes to obtain a suspension of hydroxypropyl-β-cyclodextrin and raw material. The suspension was then homogenized at 5000 rpm using a homogenizer, controlling the particle size range D90 to be 350-400 μm. The mixture was then spray-dried with the following parameters: inlet air temperature 120-140℃, outlet air temperature 80-110℃, air volume 80%-100%, peristaltic pump speed 40-50 rpm, compressed air pressure 0.4MPa-0.6MPa, and tower pressure 0.15-0.30 kPa. This yielded the co-treated product of quetiapine fumarate and hydroxypropyl-β-cyclodextrin. See the attached particle size distribution of the quetiapine fumarate-hydroxypropyl-β-cyclodextrin co-treated product. Figure 1 .

[0035] Example 2:

[0036] Microscopic images of the untreated active pharmaceutical ingredient and the co-treated product of quetiapine fumarate and hydroxypropyl-β-cyclodextrin in Example 1 are shown in Appendix 2. Clearly, the active pharmaceutical ingredient treated with hydroxypropyl-β-cyclodextrin exhibits shorter and rounder crystals, which are more fluid than the elongated crystals of the untreated product. The measured angles of repose for both are as follows:

[0037]

[0038] Example 3:

[0039] Preparation of quetiapine fumarate tablets: Following the formulation in Example 1, the quetiapine fumarate-hydroxypropyl-β-cyclodextrin co-processed compound was mixed in a mixer. The active pharmaceutical ingredient (API) content was determined to be 51.3%. After conversion, the mixture was fed into a wet granulator, along with other wet granulation materials (povidone, dicalcium phosphate, microcrystalline cellulose, sodium carboxymethyl starch, and lactose monohydrate). The amount of microcrystalline cellulose was slightly adjusted to ensure a total tablet weight of 100 mg. The stirring speed was set to 120 rpm, and the mixing time was 5 min for premixing. After premixing, 10 samples were taken from different locations (see...). Figure 7 The content was detected, and the individual test values ​​were all within the range of mean ± 10%, with a relative standard deviation (RSD) of 1.22%, which is much less than 5%.

[0040] Premixed sampling sites

[0041]

[0042] Example 4:

[0043] The premixed powder from Example 3 was further wet-granulated: the stirring speed was set to 120 rpm and the cutter speed to 1200 rpm. Wetting agent was added using a spray gun and peristaltic pump for 4 minutes. The stirring speed was then set back to 120 rpm and the cutter speed to 1200 rpm. Granulation continued for 1 minute after the addition of liquid. Wet granulation was performed using a 20-mesh sieve. Dry granulation was then performed using an oven at 60°C for 2 hours. Dry granulation was performed using a 20-mesh sieve. The dry granules were added to a mixer, along with the amount of magnesium stearate calculated based on the weight of the granulated material. The mixer speed was set to 4 rpm and the mixing time to 6 minutes. After mixing, 10 different points were taken (see...). Figure 8 The content was detected, and the individual test values ​​were all within ±10% of the mean, with a relative standard deviation (RSD) of 0.69%, which is much less than 5%.

[0044] Total pooling sites

[0045]

[0046] The measured angle of repose of the total mixed powder is as follows:

[0047]

[0048] The angle of repose of the total mixed powder is much less than 40°, and it has good flowability.

[0049] Example 5:

[0050] The total powder mixture from Example 4 was further compressed into tablets using a 6.0mm die, based on a theoretical tablet weight of 100mg and a hardness of 3-7kg / cm. 2 Tableting was performed. Based on the estimated number of tablets to be compressed throughout the process, 20 sampling points were taken. Seven tablets were sampled at each time point, and three tablets were measured to check the uniformity of the controlled dose. The results showed that the average value of each sampling point was between 90.0% and 110.0% of the target dose, and all individual values ​​were between 75.0% and 125.0% of the target dose. The relative standard deviation (RSD) was 1.14%, which is much less than 6%.

[0051] Central control dose unit uniformity

[0052]

[0053] Example 6:

[0054] The uncoated sheets from Example 5 above are further coated: the air inlet and outlet devices of the coating machine are turned on, the air inlet temperature is set to 55-70°C, and the coating pan main unit is turned on at 1-2 rpm to preheat the uncoated sheets. When the exhaust temperature reaches 45°C, the coating pan speed is adjusted to 3-7 rpm, and the peristaltic pump is started at 20-70 ml / min to begin coating. When the coating weight gain reaches about 2.5%, the peristaltic pump is turned off and the liquid spraying is stopped; continue drying for 15 minutes. After drying, heating is stopped, and the coated sheets are allowed to cool to room temperature to obtain the finished coated sheet product.

[0055] The dissolution curves of the coated tablets were measured and compared with those of commercially available formulations. Based on the similarity factor (F2 > 50), the dissolution trends of the two were consistent, indicating similarity. See the attached dissolution curve diagram. Figure 4 .

[0056] Comparison of dissolution results of self-developed product and commercially available formulation at pH 6.8 and 50 rpm using the paddle method.

[0057]

[0058] Example 7:

[0059] Six coated tablets were compared with commercially available formulations in terms of related substances and storage stability. Results showed that after 30 days of storage at 60℃, the self-developed product exhibited no significant change in related substances compared to day 0, remaining well below the limit. Its stability was significantly superior to that of the commercially available formulations. HPLC chromatograms of the self-developed product at 0 and 30 days are attached. Figure 5 and attached Figure 6 .

[0060] Influencing Factors - Comparison of Related Substance Detection Results between Self-Developed Products and Commercially Available Formulations under High Temperature Conditions (60℃)

[0061]

[0062]

[0063] The above embodiments are for further illustration of some preferred embodiments of the present invention and are not all embodiments. Other embodiments based on the present invention made by those skilled in the art without inventive effort are all within the scope of protection of the present invention.

Claims

1. A quetiapine fumarate composition, characterized in that, The quetiapine fumarate composition contains the following components: quetiapine fumarate-hydroxypropyl-β-cyclodextrin co-treated compound, povidone, dicalcium phosphate, microcrystalline cellulose, sodium carboxymethyl starch, lactose monohydrate, magnesium stearate, and omeprazole.

2. The quetiapine fumarate composition according to claim 1, characterized in that, The composition contains 56%–85% quetiapine fumarate-hydroxypropyl-β-cyclodextrin co-treated product, 3%–7% povidone, 2%–5% dicalcium phosphate, 2%–10% microcrystalline cellulose, 3%–7% sodium carboxymethyl starch, 2%–12% lactose monohydrate, 1% magnesium stearate, and 2%–4% weight gain from the use of Opadry coating tablets.

3. A quetiapine fumarate-hydroxypropyl-β-cyclodextrin co-treated product, characterized in that, The quetiapine fumarate-hydroxypropyl-β-cyclodextrin co-treated product comprises 33%–50% quetiapine fumarate and 50%–67% hydroxypropyl-β-cyclodextrin.

4. The method for preparing the quetiapine fumarate-hydroxypropyl-β-cyclodextrin co-treated product according to claim 3, characterized in that, The preparation method steps are as follows: In a preparation container, after adding purified water, hydroxypropyl-β-cyclodextrin is added first and stirred to dissolve. Then, quetiapine fumarate raw material is added, with a feeding ratio of hydroxypropyl-β-cyclodextrin to quetiapine fumarate raw material of 1:1 to 2:

1. Stirring is started to obtain a suspension of hydroxypropyl-β-cyclodextrin and raw material. The suspension is then homogenized using a homogenizer, and the particle size range D90 needs to be controlled to be 350 to 400 μm. Finally, spray drying is performed to obtain the co-treated product of quetiapine fumarate and hydroxypropyl-β-cyclodextrin.

5. A method for preparing quetiapine fumarate tablets, characterized in that, The quetiapine fumarate-hydroxypropyl-β-cyclodextrin co-treated product, povidone, dicalcium phosphate, microcrystalline cellulose, sodium carboxymethyl starch, and lactose monohydrate were premixed, wet granulated, and wet sizing in a wet granulator, then dried in an oven. After dry sizing, magnesium stearate was added for total mixing, tableting, and coating.

6. A method for preparing quetiapine fumarate tablets, characterized in that, The proportions of materials used in the method are as follows: The product contains 56%–85% quetiapine-hydroxypropyl-β-cyclodextrin co-treated material, 3%–7% povidone, 2%–5% dicalcium phosphate, 2%–10% microcrystalline cellulose, 3%–7% sodium carboxymethyl starch, 2%–12% lactose monohydrate, and 1% magnesium stearate. The coated tablets use Opadryl for a 2%–4% weight gain.

7. A quetiapine fumarate tablet, characterized in that, The quetiapine fumarate tablets are prepared using any one of the methods described in claims 4 to 6.

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