A novel formulation for palbociclib tablet

Abstract

This invention introduces a stable oral tablet dosage form comprising palbociclib or its pharmaceutically acceptable salts, along with at least one excipient. By adjusting the amount of excipients, the formulation enhances the flow and granulation properties, ensuring uniform die filling and precise weight control during tablet production. Specifically, it involves a process for producing without flow and adhesive problems that can be dry granulated powder comprising palbociclib, to prepare storage-stable tablets having an acceptable in-vitro dissolution profile.

Description

[0001] A NOVEL FORMULATION FOR PALBOCICLIB TABLET

[0002] Technical field:

[0003] The present invention relates to an oral solid dosage form comprising palbociclib or pharmaceutically acceptable salts thereof, and at least one excipient. The type and amount of excipient used in the formulation improves the flow and granulation properties of the drug. In particular, the present invention relates to a method for producing a free- flowing composition that palbociclib is dry granulated with one or more pharmaceutically acceptable excipients except that succinic acid to produce storage stable tablets with an acceptable in vitro dissolution profile.

[0004] Prior Art:

[0005] Palbociclib is a potent and selective inhibitor of cyclin-dependent kinases CDK4 and CDK6. It is indicated for the treatment of breast cancer which is the most common cancer in women. The chemical name of Palbociclib is 6-acetyl-8-cyclopentyl-5-methyl-2-{[5- (piperazin-1-yl)pyridin-2yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one, and its empirical formula is C24H29N7O2 with the following structural formula;

[0006] Palbociclib

[0007] Palbociclib is approved in the United States for the treatment of hormone receptor (HR)- positive, human epidermal growth factor 2 (HER2)-negative advanced or metastatic breast cancer in combination with letrozole as initial endocrine therapy or in combination with Fulvestrant after disease progression on endocrine therapy. Palbociclib is approved as immediate release capsules and tablets and marketed as a free base under the brand name Ibrance® (Pfizer). The capsules and tablets are approved in 75 mg, 100 mg and 125 mg strengths. Palbociclib and pharmaceutically acceptable salts thereof are disclosed in WO 2003 / 062236 A1 which describes the preparation of palbociclib as its hydrochloride salt. WO 2005 / 005426 A1 describes the preparation of palbociclib free base and various mono- and di-acid addition salts thereof including various polymorphic forms of the isethionate salt. WO 2014 / 128588 A1 teaches that palbociclib free base is provided by salt break procedures. Other crystalline forms and an amorphous form of Palbociclib HOI are described in WO 2016 / 066420. WO 2016 / 092442 and WO 2016 / 090257 describe crystalline forms of Palbociclib salts including phosphate, acetate, lactate, maleate, fumarate, citrate, succinate, L-tartarate, glutarate, adipate, glyconate, diesylate, hippurate, esylate and isethionate.

[0008] WO 2016 / 193860 A1 describes a solid dosage form that includes palbociclib, a water- soluble acid, and a pharmaceutically acceptable carrier. The solid dosage form contains approximately 10-35 wt% palbociclib and 5-25 wt% of a water-soluble acid, which may be succinic acid, malic acid, or tartaric acid.

[0009] The composition disclosed in WO 2016 / 070833 A1 includes a solid dispersion prepared with Palbociclib, a disintegrant, a diluent, a binder, a lubricant, and a glidant.

[0010] WO 2016 / 070834 A1 discloses a composition comprising Palbociclib or a salt thereof, and a pharmaceutically acceptable excipient as a carrier, wherein the salt is selected from the group consisting of hydrochloride and isethionate.

[0011] WO 2016 / 156070 A1 discloses a crystalline palbociclib having a specific surface area in the range of from 2.1 to 6.0 m2 / g as determined by BET-nitrogen adsorption analysis. The said publication discloses a pharmaceutical composition comprising an effective amount of Palbociclib and a pH modifier which is a weak acid, preferably an organic acid. The pH modifier is selected from the group consisting of succinic acid, tartaric acid, ascorbic acid, citric acid, lactic acid, malic acid, fumaric acid, aspartic acid, glutamic acid, and mixtures thereof. Most preferably the pH modifier is succinic acid or a mixture of succinic acid and tartaric acid.

[0012] WO 2017 / 036390 A1 discloses a pharmaceutical composition containing a Palbociclib solid dispersion, comprising a solid dispersion formed by Palbociclib and an organic carrier and at least one pharmaceutical excipient, wherein Palbociclib is amorphous.

[0013] WO 2017 / 166451 A1 discloses a pharmaceutical formulation of palbociclib, comprising a palbociclib free base or a pharmaceutically acceptable salt thereof and an acidic auxiliary material, wherein the acidic auxiliary material is one or more selected from the group consisting of tartaric acid, fumaric acid, succinic acid, citric acid, lactic acid and malic acid.

[0014] WO 2019 / 020715 A1 discloses a pharmaceutical granulate composition comprising a therapeutically effective dose of crystalline Palbociclib and one or more pharmaceutically acceptable excipients, wherein the Palbociclib crystals are needles with a surface area between 6 and 15 m2 / g, and a particle size distribution d(0.9) between 5 and 50 micrometers.

[0015] WO 2021 / 220295 A1 discloses immediate release pharmaceutical composition comprising Palbociclib or a pharmaceutically acceptable salt thereof, a water soluble acid and one or more pharmaceutically acceptable excipients, wherein the composition contains Palbociclib and water soluble acid in separate layers.

[0016] WO 2022 / 029799 A1 discloses solid dosage forms of Palbociclib comprising at least one compound selected from the group consisting of sulphur-containing amino acid or peptide, and at least one vitamin having antioxidant properties.

[0017] Palbociclib is a non-hygroscopic yellow to orange crystalline powder that is classified as BCS Class II compound based on the Biopharmaceutical Classification System. This means that the solubility of Palbociclib is a critical and rate-limiting factor in achieving adequate bioavailability of the finished product.

[0018] Palbociclib is a dibasic compound and has two basic groups with pKa’s of approximately 7.3 (the secondary piperazine nitrogen) and 4.1 (the pyridine nitrogen). It is water soluble at low pH (2.1-4.5), while solubility decreases dramatically at pH above 4.5. Palbociclib has poor water solubility (9 pg / ml) at pH 7.9. According to the EPAR, the maximum dose of 125 mg is not completely soluble in 250 mL of media from pH 1 to pH 6.8, but is completely soluble at pH values below 4.3. The solubility of Palbociclib free base is pH dependent. Therefore, it is very sensitive to the pH of the gastrointestinal tract during its dissolution in the tract.

[0019] With oral administration of such poorly soluble substances, the dissolution rate is the limiting factor in drug absorption. Therefore, there is still a need to improve the dissolution rate in pharmaceutical processing, which has a major impact on bioavailability.

[0020] Product development studies have shown that, palbociclib bulk drug is a loose powder that easily adheres and agglomerates, resulting in poor fluidity. Therefore, it was difficult for content uniformity in preparation products prepared to meet standard requirements, and in particular, the uniformity is more difficult to control in a production scale. It is also known from the literature that the active ingredient palbociclib is prone to degradation with the formation of an acid adduct of the water-soluble acid with the piperazinyl moiety of palbociclib. Ensuring high stability of the product, especially in storage stability, is a very critical problem for pharmaceutical products.

[0021] The present invention addresses and provides a solution to these problems. Thus, the present inventors have developed a free-flowing and non-sticky composition that can be dry granulated into storage stable tablets with an acceptable in vitro dissolution profile.

[0022] Description of the Invention:

[0023] The present invention relates to a stable oral tablet dosage form comprising palbociclib or pharmaceutically acceptable salts thereof.

[0024] According to one embodiment of the present invention, there is provided a tablet formulation for producing a dry granulated powder comprising palbociclib or pharmaceutically acceptable salts thereof, and at least one excipient.

[0025] According to one embodiment of the present invention, there is provided a formulation for producing a free-flowing composition that palbociclib active substance is dry granulated with one or more pharmaceutically acceptable excipients except that succinic acid to produce storage stable tablets with an acceptable in vitro dissolution profile.

[0026] According to one embodiment of the present invention, there is provided a stable oral pharmaceutical tablet composition comprising therapeutically effective amount of palbociclib, wherein palbociclib active substance is dry granulated with one or more pharmaceutically acceptable excipients except that succinic acid, and succinic acid and one or more pharmaceutically acceptable excipients are mixed with the prepared granules as an exragranular phase; wherein the said tablet composition comprises palbociclib to succinic acid ratio between 2.1 :1 to 3:1 (w / w), preferably between 2.2:1 to 2.5:1 (w / w).

[0027] According to one embodiment of the present invention, there is provided a stable oral pharmaceutical tablet composition comprising therapeutically effective amount of palbociclib, wherein the tablet core comprising: Palbociclib and one or more pharmaceutical acceptable excipient which are present in intragranular phase, and succinic acid, magnesium stearate and one or more pharmaceutically acceptable excipient which are present in extragranular phase.

[0028] According to another embodiment of the present invention, wherein the prepared intragranular phase mixture was slugged with a compression of maximum 200 Newton hardness. According to another embodiment of the present invention, the prepared intragranular phase mixture was slugged with a compression of maximum 200 Newton hardness wherein the prepared final tablet composition has a release rate of greater than 80% at 30 minutes when tested in USP 2 apparatus with paddles spinning at 75 rpm, in 900 mL of 0.1 N HCI at a temperature of 37°C.

[0029] The pharmaceutical tablet composition in accordance with the present invention is used as an effective medication for treating breast cancer.

[0030] When formulating a compound into a tablet or other solid dosage form, it is desirable to develop a formulation which is storage stable at temperatures and relative humidity levels above those typically encountered. Other desirable properties in a formulation may also be sought, such as fast dissolution so that the tablet quickly dissolves and the drug is available for absorption. Accordingly, good storage stability and fast dissolution were, inter alia, features that were sought as desirable characteristics for the instant invention. The present invention confidently aims to produce a stable and solid oral pharmaceutical composition that contains palbociclib. This composition also have an in-vitro dissolution profile that is comparable to that of Ibrance® Tablets.

[0031] Pharmaceutical companies strive to improve the quality of their products and accelerate drug development, while at the same time seeking innovative ways to reduce costs. The three commercially important processes for making compressed tablets are wet granulation, direct compression and dry granulation (slugging or roller compaction). The method of preparation and choice of excipients are carefully selected to achieve the desired physical characteristics of the tablet formulation, allowing for efficient compression of the tablets.

[0032] Wet granulation process involves mixing pre-weighed active substance with one or more other ingredients, such as a diluent. The mixture is then mixed with a liquid, such as water or ethanol, which causes the particles to agglomerate into a moist mass. The liquid may contain a binder. The wet mass is screened to produce granules, which are then dried. The dry granules are screened to produce granules of a predetermined size. The granules are then typically mixed with a solid lubricant and optionally other ingredients. Finally, the lubricated granules and any other extra-granular ingredients are compressed into a tablet, which may then be coated.

[0033] Dry granulation process involves fewer steps than wet granulation and does not require contact with a liquid or drying, making it well suited to formulating water and heat sensitive drugs. In the dry granulation method, the active substance and one or more other ingredients are mixed and then compressed in a first compression step. There are two conventional first compression techniques. One is roller compaction, in which the mixture is fed between rollers that compress the mixture into tablets; the other is slugging, in which the mixture is compressed into slugs, which are tablet-like forms typically larger than tablets intended for human consumption also known as briquettes, flakes or ribbons. The resulting sheets or slugs are then crushed into granules, mixed with extragranular phase and compressed in a second compression stage to produce the final tablet.

[0034] Experimental testing during product development has shown that palbociclib active ingredient has the characteristics of a loose powder that is prone to adhesion and agglomeration, resulting in inadequate flowability. As a result, achieving content uniformity in prepared products to meet standard specifications has been challenging, particularly in large-scale production where uniformity control becomes more difficult.

[0035] Porous and free-flowing granules are generally desired in the pharmaceutical industry because, for example, porous granules can be used to produce improved tablets. Such tablets can disintegrate much faster than, for example, tablets made from dense granules. There is, therefore, a need for improved tablet compositions and associated manufacturing methods which will enable tablets to be produced which have both sufficient hardness to resist breakage, chipping and abrasion and adequate dissolution and disintegration characteristics required for immediate release tablets.

[0036] In accordance with some aspects of the present disclosure, there is provided, as described herein, pharmaceutical dosage form tablets comprising therapeutically effective amount of palbociclib or pharmaceutically acceptable salt thereof, wherein palbociclib active substance is dry granulated with one or more pharmaceutically acceptable excipients other than succinic acid, and the prepared granules are mixed with exragranular phase comprising succinic acid, wherein the said tablet composition comprises palbociclib to succinic acid ratio between 2.1 :1 to 3:1 (w / w). The prepared tablets exhibit rapid dissolution rate, sufficient hardness to resist table chipping or crumbling during packaging and storage, and sufficient abrasion resistance to resist erosion or chipping during coating. In accordance with some other aspects of the present disclosure, there is provided, as described herein, a processes for preparing the pharmaceutical stable dosage form tablets comprising palbociclib active substance from granules. The term "active substance" or "active ingredient" means any component which is intended to have pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease, or to affect the structure or any function of the body of humans or other animals. In the present invention, the active substance is palbociclib or its pharmaceutically acceptable salts thereof. Unless otherwise indicated herein, palbociclib refers to the free base form of 6-acetyl-8-cyclopentyl-5-methyl-2-(5- piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d] pyrimidin-7-one, which may be in crystalline or amorphous form, or a mixture of amorphous and crystalline forms.

[0037] The term “therapeutically effective amount” refers to the amount of palbociclib or its pharmaceutically acceptable salts, esters and solvates thereof, that is sufficient to affect a treatment, as defined herein when administered to a subject in need of such treatment. In relation to the treatment of cancer, a therapeutically effective amount refers to that amount which has the effect of (1) reducing the size of the tumour, (2) inhibiting (i.e. slowing to some extent, preferably stopping) tumour metastasis, (3) inhibiting (i.e. slowing to some extent, preferably stopping) tumour growth or invasiveness, and / or (4) alleviating (or preferably eliminating) one or more signs or symptoms associated with the cancer. In the present invention, the proposed tablet composition comprises 75 mg, 100 mg or 125 mg palbociclib.

[0038] The term "immediate release" as used herein refers to the release of the active ingredient immediately upon reaching the stomach.

[0039] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms in the exercise of sense medical judgement, are suitable for contact with the tissues of mammals, in particular humans, without excessive toxicity, irritation, allergic reaction and other problematic complications, consistent with a reasonable benefit / risk ratio.

[0040] The tablets may contain inert materials known as excipients in addition to active substances. The pharmaceutical compositions described in this invention include one or more pharmaceutically acceptable excipients. The term "excipient" refers to any substance that is not a therapeutic agent but is used as a carrier or vehicle for delivering a therapeutic agent to a subject. It can also be combined with a therapeutic agent to improve its handling or storage properties or to facilitate the formation of a dose unit of the composition. Excipients are substances added to a composition to enhance its appearance, texture or taste. They comprise of binders, disintegrants, taste enhancers, solvents, thickening or gelling agents (and any neutralizing agents, if necessary), penetration enhancers, solubilizing agents, wetting agents, antioxidants, lubricants, emollients, emulsifying agents, surfactants, substances added to mask or counteract a disagreeable odor, fragrances or taste.

[0041] A filler / diluent is an inert ingredient that may be used as a bulking agent to reduce the concentration of the active ingredient in the final formulation. Tablets typically contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, compressible sugar, microcrystalline cellulose, powdered cellulose, starch, pregelatinized starch, dextran, dextrin, dextrose, maltodextrin, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, magnesium carbonate, magnesium oxide, poloxamers, polyethylene oxide, hydroxypropyl methyl cellulose, and mixtures thereof. Different types of microcrystalline cellulose are also suitable for use in the formulations described herein. The types of microcrystalline cellulose used are: Avicel® PH 101 , PH 102, PH 103, PH 105, PH 112, PH113, PH200, PH301 , and other types of microcrystalline cellulose, such as silicified microcrystalline cellulose (SMCC). In some embodiments, the diluent is selected from a group of substances that includes microcrystalline cellulose, lactose monohydrate, mannitol, sorbitol, xylitol, magnesium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, or mixtures thereof. In the present invention, the diluent comprises microcrystalline cellulose. Diluents frequently comprise from 25 wt% to 75 wt% of the solid dosage form, and in the present invention diluents comprise from 54 wt% to 64 wt% of the dosage form.

[0042] Solid dosage forms typically contain disintegrants, such as sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch, and sodium alginate. The carrier in some embodiments contains at least one disintegrant, which may be selected from crospovidone, croscarmellose sodium and sodium starch glycolate. In the present invention, the disintegrant is crospovidone. Disintegrants frequently comprise from 4 wt% to 20 wt%, and in the present invention disintegrants comprise from 4 wt% to 9 wt% of the dosage form.

[0043] Lubricants are added to compositions for tableting in order to reduce the friction between the surfaces of manufacturing equipment and that of organic solids in the tablet composition, promote ejection from the tablet press, affect the dynamics of dry granulation and tableting processes, and affect the mechanical properties of tablets. Lubricants may suitably be added to the pre-blend prior to granulation thereby forming intragranular lubricant. Additionally, lubricants may be combined with granulated preblend prior to tableting thereby forming extragranular lubricant. Solid dosage forms commonly contain one or more lubricants, such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, mixtures of magnesium stearate with sodium lauryl sulfate, or mixtures of two or more of these. In the present invention, the lubricant is magnesium stearate and the solid dosage form is a tablet comprising magnesium stearate in the extragranular phase. Lubricants frequently comprise from 0.25 wt% to 10 wt%, and in the present invention lubricant comprise from 0.5 wt% to 3 wt% of the dosage form.

[0044] Glidants are added to increase the flowability of the powder. It is typically used to help ensure that the component mixture is evenly and uniformly filled into the dies prior to compression. Tablets may also compromise glidants, such as silicon dioxide, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, talc, and other forms of silicon dioxide, such as aggregated silicates and hydrated silica. In the present invention, the glidant is colloidal silicon dioxide. Glidants frequently comprise from 0.1 wt% to 10 wt%, and in the present invention glidant comprise from 0.1 wt% to 2 wt% of the dosage form.

[0045] In pharmaceutical products, succinic acid, as an excipient, is also used to control acidity (pH modifier) or as a counter ion. Succinic acid is used as a water-soluble acid present in the composition refers to an acid that has a solubility of at least 0.2% by weight in water at 25°C.

[0046] The tablets of the present disclosure (tablet cores) are preferably coated with a filmcoating to provide for tablets that are predominantly tasteless and odorless, and are easy to swallow. Further, film coating prevents dust formation during packaging and ensures robustness during transportation.

[0047] In the present invention, the formulation of tablet comprises 22 wt% to 25 wt% of palbolciclib active substance, preferably 22.9 wt% of the dosage form. The remaining components consist of 7 wt% to 11 wt% succinic acid, 54 wt% to 64 wt% diluent; 4 wt% to 9 wt% disintegrant; 0.5 wt% to 3 wt% lubricant; and 0.1 wt% to 2 wt% glidant of the dosage form.

[0048] Finding suitable excipients for a particular active substance and determining the appropriate manufacturing process for the combination of excipient and active substance can be a challenging task when designing a pharmaceutical product such as a tablet. Developing a stable formulation that can withstand higher temperatures and relative humidity levels than those typically encountered is essential when formulating a compound into a tablet or another solid dosage form. It is also important to consider other desirable properties, such as fast dissolution, to ensure that the drug is quickly available for absorption. The present invention achieves good storage stability and fast dissolution, among other desirable characteristics.

[0049] Examples:

[0050] The scope of present invention is the preparation of a stable pharmaceutical dosage form for oral administration comprising Palbociclib or pharmaceutically acceptable salts thereof, and exhibiting an immediate drug release profile.

[0051] Example 1.

[0052] The tablet containing Palbociclib can be produced using dry granulation method. This method includes slugging, where an additive is added to the active ingredient and mixed to make it homogeneous. The mixture is then compressed, molded, and pulverized to an appropriate size for granulation. This makes it suitable for drugs that are unstable to solvent for heat during drying, as the need for solvents and drying steps is eliminated.

[0053] Table 1. Unit formula for Palbociclib Tablet using dry granulation method

[0054] For 125mg, 10Omg, 75mg tablet % Component

[0055] F-01 F-02 F-03

[0056] Intragranular phase

[0057] Palbociclib 22.9 22.9 22.9

[0058] Microcrystalline cellulose 28-32 28-32 28-32

[0059] Crospovidone 3-6 3-6 3-6

[0060] Colloidal silicon dioxide 0.1-2 0.1-2 0.1-2

[0061] Extragranular phase Succinic Acid 8 5 10

[0062] Microcrystalline Cellulose 26-32 26-32 26-32

[0063] Crospovidone 1-3 1-3 1-3

[0064] Magnesium stearate 0.5-3 0.5-3 0.5-3

[0065] The required amounts of Palbociclib, microcrystalline cellulose, crospovidone and colloidal silicon dioxide are mixed for 15 minutes. The mixture obtained is slugged with a compression of maximum 200 Newton hardness and the resulting briquette tablet or slugged blends are subjected to dry grinding to obtain the desired size. Succinic acid is added to the granules obtained after the dry grinding stage and mixed for 20 minutes. Crospovidone, microcrystalline cellulose and magnesium stearate are added to the obtained powder mixture. The final blends were compressed and film coated. In the experimental studies, a decrease in in-vitro dissolution profiles was observed in tablets which are slugged with a compression of above 200 Newton hardness.

[0066] Example 2. Comparative Products- Dry granulation with succinic acid

[0067] Table 2. Unit formula for Palbociclib Tablet using dry granulation with succinic acid

[0068] For 125mg, 100mg, 75mg tablet % Component

[0069] F-04

[0070] Intragranular phase Palbociclib 22.9

[0071] Microcrystalline cellulose 28-32

[0072] Crospovidone 3-6

[0073] Colloidal silicon dioxide 0.1-2

[0074] Succinic Acid 10

[0075] Extragranular phase Microcrystalline Cellulose 26-32

[0076] Crospovidone 1-3

[0077] Magnesium stearate 0.5-3

[0078] The tablets are obtained as described in Example 1. The difference is the presence of succinic acid in the intragranular phase. The required amounts of Palbociclib, microcrystalline cellulose, crospovidone, colloidal silicon dioxide and succinic acid are mixed for 15 minutes. The mixture obtained is slugged and the resulting briquette tablets are subjected to dry grinding. Crospovidone, microcrystalline cellulose and magnesium stearate are added to the obtained powder mixture. The final blends were compressed and film coated.

[0079] Example 3. In-Vitro Dissolution

[0080] Drug dissolution represents a critical factor affecting the rate of systemic absorption. A variety of in vitro methods have been developed for assessing the dissolution properties of pharmaceutical formulations, and dissolution testing is sometimes used as a surrogate for the direct evaluation of drug bioavailability. See, e.g., Emmanuel et al., Pharmaceutics (2010), 2:351-363, and references cited therein. Dissolution testing measures the percentage of the active substance that has been released from the drug product (i.e., tablet or capsule) and dissolved in the dissolution medium under controlled testing conditions over a defined period of time. To maintain sink conditions, the saturation solubility of the drug in the dissolution media should be at least three times the drug concentration. For low solubility compounds, dissolution may sometimes be determined under non-sink conditions. Dissolution is affected by the properties of the active substance (e.g., particle size, crystal form, bulk density), the composition of the drug product (e.g., drug loading, excipients), the manufacturing process (e.g., compression forces) and the stability under storage conditions (e.g., temperature, humidity).

[0081] In the present invention, the tablets were tested in a USP 2 apparatus with paddles spinning at 75 rpm, in 900 mL of 0.1 N HCI at a temperature of 37°C. An in-vitro comparative dissolution test, performed for test and reference products in accordance to the Guideline on Investigation of Bioequivalence, was performed using the chosen dissolution conditions (900 mL dissolution medium, paddle at 75 rpm at 37°C ±0.5°C at 0.1 N HCI medium). The above exemplified compositions (Formulations F-01 to F-04) comprising palbociclib were tested in vitro and they were compared with a commercial reference product Ibrance © Tablet.

[0082] Comparative dissolution data were generated for the palbociclib tablet prepared using the dry granulation method of Example 1 and Example 2 (F-01 to F-04) with reference product Ibrance ® Tablet. The results of the dissolution test for tablets prepared by different production methods are shown in Figure 1.

[0083] The dissolution profiles were compared; the dissolution profiles obtained were evaluated by similarity factor (fp) (Helmy & Bedaiwy, 2013). An fp value between 50 and 100 suggests that the all-dissolution profiles are similar (EMEA Guideline on the Investigation of Bioequivalence, 2010). The similarity factor (fp) values of test products (Formulations F-01 , F-03 and F-04) and reference product (Ibrance® Tablet) for the different pH media are found between 50 and 100. On the other hand, the f2values of test product F-02 and reference product were found to be less than 50, indicating that the amount of succinic acid affects the in vitro dissolution of palbociclib.

[0084] Example 4. Stress Studies

[0085] Firstly, accelerated stability tests are performed by storing a product in stress conditions. These tests allow predicting the shelf-life of the product over the years when it will be stored in normal storage conditions. Forced degradation studies of Palbociclib tablets were conducted in accordance with the ICH guidelines. Palbociclib tablets (Formulations F-01 , F-03 and F-04) were exposed to thermal stress (80°C for 3 days), photolytic stress (ultraviolet light 200 W-hours per square meter, and fluorescence light 1.2 million lux- hours for 8 days) and humidity stress (40 °C & 75%±5% Relative Humidity for 7 days). Especially in the results obtained from the studies on Palbociclib compositions, it was observed that the amount of degradation products in the tablets obtained by dry granulation with succinic acid in the intragranular phase (F-04) was 2 times higher than the tablets obtained by dry granulation without succinic acid in the intragranular phase (F-01 and F-03).

[0086] Example 5. Stability Studies

[0087] The stability of a drug substance is an important factor in the manufacture of safe and effective pharmaceutical products. Stability studies are required to be submitted by any applicant seeking approval for a new pharmaceutical product. The rules in force (e.g. "Note for Guidance on Impurities in New Drug Products" CPMP / ICH / 2738 / 99, issued by EMEA, European Medicines Agency) provide strict limitations for impurities, nevertheless it is better to prevent or reduce as possible the degradation to avoid the exposure of patients to substances.

[0088] The stability of a pharmaceutical dosage form is related to maintaining its physical, chemical, microbiological, therapeutic, and toxicological properties when stored, i.e., in a particular container and environment. For the solid dosage forms of the present invention, the formation of an acid adducts of the piperazinyl moiety of palbociclib and the water-soluble acid is a key degradant that is monitored to assess storage stability.

[0089] It is known that many drugs exhibit poor or modest shelf stability. The presence of degradation products of these drugs can give rise to efficacy or toxicity issues, but even if they do not, the diminution of the concentration of a drug as a result of its degradation is inherently undesirable, as it makes therapy with the drug less certain. Stability issues can be caused by environmental factors such as humidity, temperature and the like. However, degradation may result from, or be accelerated by, interactions of drug substances with pharmaceutical excipients or impurities contained in any of these excipients.

[0090] Stability tests in this case were performed according to the EMEA Guideline on Stability Testing (CPMP / QWP / 122 / 02, rev 1), i.e. by maintaining the product in its container at a temperature of 40°C ± 2°C and 75% ± 5 %RH (Relative Humidity) for six months and at a temperature of 25°C ± 2°C and 60% ± 5% RH for twenty-four months.

[0091] In the stability studies, no unexpected degradation impurity formation was observed especially in the products obtained by dry granulated palbociclib active substance with one or more pharmaceutically acceptable excipients except that succinic acid. The resulting tablets showed appropriate content uniformity results at the initial state and throughout the stability studies. The formulation is stable based on chemical / physical stability with an accelerated and long-term stability test conditions. FIGURES

[0092] Figure 1. In-vitro dissolution profile of Test Products (F-01 to F-04) with reference product Ibrance ® Tablet

Claims

CLAIMS1 . A stable oral pharmaceutical tablet composition comprising therapeutically effective amount of palbociclib or pharmaceutically acceptable salt thereof, wherein(i) palbociclib active substance is dry granulated with one or more pharmaceutically acceptable excipients except that succinic acid,(ii) succinic acid and one or more pharmaceutically acceptable excipients are mixed with the prepared granules as an exragranular phase wherein the said tablet composition comprises palbociclib to succinic acid ratio between 2.1 :1 to 3:1 (w / w).

2. The stable pharmaceutical composition according to claim 1 , wherein the said tablet composition comprises palbociclib to succinic acid ratio between 2.2:1 to 2.5:1 (w / w).

3. The stable pharmaceutical composition according to claim 1 , wherein palbociclib is free base.

4. The stable pharmaceutical composition according to claim 3, wherein the formulation of said tablet comprises 22 wt% to 25 wt% of palbociclib active substance of the dosage form.

5. The stable pharmaceutical composition according to claim 1 , wherein the formulation of said tablet comprises 7 wt% to 11 wt% of succinic acid of the dosage form.

6. The stable pharmaceutical composition according to claim 1 , wherein one or more pharmaceutically acceptable excipient is selected from the group comprising of diluent, disintegrant, lubricant and glidant.

7. The stable pharmaceutical composition according to claim 6, wherein the formulation of said tablet comprises 54 wt% to 64 wt% diluent; 4 wt% to 9 wt% disintegrant; 0.5 wt% to 3 wt% lubricant; and 0.1 wt% to 2 wt% glidant of the dosage form.

8. The stable pharmaceutical composition according to claim 7, wherein diluent is selected from lactose, mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, pregelatinized starch, dextrates, dextran, dextrin, dextrose, maltodextrin, calcium carbonate, dibasic calcium phosphate, calcium sulfate, magnesium carbonate, magnesium oxide, poloxamers, polyethylene oxide, hydroxypropyl methyl cellulose or mixtures thereof.

9. The stable pharmaceutical composition according to claim 8, wherein diluent is microcrystalline cellulose.

10. The stable pharmaceutical composition according to claim 7, wherein disintegrant is selected from sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl- substituted hydroxypropyl cellulose, starch, pregelatinized starch, and sodium alginate or mixtures thereof.

11. The stable pharmaceutical composition according to claim 10, wherein disintegrant is crospovidone.

12. The stable pharmaceutical composition according to claim 7, wherein lubricant is selected from magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, mixtures of magnesium stearate with sodium lauryl sulfate, or mixtures of two or more of these.

13. The stable pharmaceutical composition according to claim 12, wherein lubricant is magnesium stearate.

14. The stable pharmaceutical composition according to claim 1 , wherein the tablet core comprising: i. Palbociclib and one or more pharmaceutical acceptable excipient are present in intragranular phase, ii. succinic acid, magnesium stearate and one or more pharmaceutically acceptable excipient are present in extragranular phase.

15. The stable pharmaceutical composition according to claim 14, wherein the prepared intragranular phase mixture was slugged with a compression of maximum 200 Newton hardness.

16. The stable pharmaceutical composition according to any of preceding claims, wherein the said final tablet composition has a release rate of greater than 80% at 30 minutes when tested in USP 2 apparatus with paddles spinning at 75 rpm, in 900 mL of 0.1 N HCI at a temperature of 37°C.

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