RO135833A2 - Pharmaceutical compositions containing pramiracetam hydrate, process for preparing the same and use thereof - Google Patents

Abstract

The invention relates to a pharmaceutical composition containing Pramiracetam hydrate to be used in the treatment of memory and attention deficit. According to the invention, the composition comprises Pramiracetam hydrate, as an active ingredient, with a water content of 6.5...11.5% by weight as related to the weight of the active ingredient and at least one pharmaceutically acceptable excipient, the composition being in solid form, preferably as a compressed tablet for oral administration.

Description

Pharmaceutical compositions containing Pramiracetam hydrate, process for their preparation and uses

TECHNICAL FIELD

The present invention relates to pharmaceutical compositions containing Pramiracetam hydrate, their manufacturing process and their uses.

STATE OF THE ART

Pramiracetam is a synthetic derivative of piracetam, the first laboratory-created nootropic, but it is significantly more potent than other previously used derivatives.

Acid addition salts of pramiracetam (1-Pyrrolidineacetamide, N-[2-[bis(1methylethyl)amino]-ethyl]-2-oxo) and their monohydrate are described in US4145347A.

Pramiracetam is a central nervous system stimulant and nootropic agent belonging to the racetam family of drugs. It is marketed by Menarini under the brand name Pramistar as a treatment for memory and attention deficits due to aging or associated with neurodegenerative and vascular dementia in Italy and some Eastern European countries. Pramistar contains Pramiracetam sulfate, microcrystalline cellulose, precipitated silica, crospovidone, calcium stearate, hydroxypropylcellulose, titanium dioxide, hydroxypropyl methylcellulose, polyethylene glycol 3350, polyethylene glycol 400.

Pramiracetam sulfate is very soluble in water. There are several problems caused by the high solubility and hygroscopic nature of Pramiracetam sulfate. One problem is that it is difficult to process Pramiracetam sulfate by wet granulation using a high shear granulator. When binding water is added to the high shear granulator, the API (Pramiracetam hydrate) immediately dissolves and generates a highly agglomerated and sticky mass that cannot be further granulated. Wet granulation in the Fluidized Bed Processor (FBP) is also difficult because the granules obtained by FBP have a low bulk density

Another problem is that compressing granulated pramiracetam sulfate with water is difficult. Tablets have problems sticking to the faces of the punches. Bonding can also be seen on the turret plate.

Also, under normal conditions of % 30-60% relative humidity, the granules tend to corrode the metal parts of the compactor.

A feasible option for using pramiracetam sulfate is solvent granulation. However, this requires the area and equipment to be flame/explosion resistant, which is difficult to achieve due to high costs and other associated risks.

Pramiracetam hydrate with a water content of between 5.6 and less than 6.5% is known together with a pharmaceutically acceptable excipient. However, by using Pramiracetam hydrate with a water content between 5.6 and less than 6.5% in a pharmaceutical composition, the resulting tablets have low hardness. Moreover, serious sticking of API to machine parts (turret plate, press feed parts, punches) was observed. Also, another problem noted is that the minimum disintegration of the base tablet is 11 minutes.

The technical problem to be solved is to provide a pharmaceutical composition comprising Pramiracetam hydrate as an active ingredient which eliminates all the problems mentioned above. >

The technical problem is solved by the present invention by providing pharmaceutical compositions comprising as an active ingredient Pramiracetam hydrate with a water content of not more than 6.5% w/w based on the weight of the active ingredient and at least one acceptable excipient of pharmaceutical point of view. In particular, the pharmaceutical composition comprises as active ingredient Pramiracetam hydrate in which the water content is from 6.5% w/w to 11.5% w/w based on the weight of the active ingredient, preferably from 7, 5% to 8.7% w/w based on the weight of the active ingredient and at least one pharmaceutically acceptable excipient.

SUMMARY OF THE INVENTION

The present invention provides pharmaceutical compositions comprising as an active ingredient Pramiracetam hydrate with a water content greater than 6.5% w/w based on the weight of the active ingredient and at least one pharmaceutically acceptable excipient. In particular, there is provided a pharmaceutical composition comprising as an active ingredient Pramiracetam hydrate in which the water content is from 6.5% w/w to 11.5% w/w, preferably from 7.5 % to 8.7% w/w based on the weight of the active ingredient and at least one pharmaceutically acceptable excipient.

The term active ingredient refers to a compound of Pramiracetam together with associated water, for example embedded in its crystal as a hydrate or adsorbed on the surface of Pramiracetam crystals (hydrate). The active ingredient does not refer to any pharmaceutically acceptable excipient, for example a bulking agent, a disintegrating agent, a binder, a release agent, a sliding agent and a lubricating agent.

The invention also provides a process for obtaining the pharmaceutical composition comprising Pramiracetam hydrate with a water content of not more than 6.5% w/w and 11.5% w/w, preferably from 7.5% to 8 .7% w/w based on the weight of Pramiracetam hydrate and at least one pharmaceutically acceptable excipient.

The invention also provides the use of the pharmaceutical compositions in therapy, more specifically for treating memory and attention deficits due to aging or associated with neurodegenerative disorder and vascular dementia.

Description of Drawings:

Fig 1: Pramiracetam hydrate crystal surface before hydration

Fig 2: Pramiracetam hydrate crystal surface after water treatment

Fig 3: Microscopic observation of the Pramiracetam hydrate crystal surface treatment at two levels of surface treatment compared to the initial surface of the crystals Fig 4: Comparison between the dissolution profile of the reference compound (Pramistar® containing Pramiracetam sulfate) and the composition according to Example 3 (composition containing Pramiracetam monohydrate according to the invention).

Abbreviations used throughout the description:

API stands for active pharmaceutical ingredient which is Pramiracetam hydrate

PSD represents particle size

WKF stands for Karl Fischer water

MMC stands for Microcrystalline Cellulose

KF stands for Karl Fisher

DETAILED DESCRIPTION

The present invention will be described in detail.

In a first aspect, the invention provides a pharmaceutical composition comprising as an active ingredient Pramiracetam hydrate with a water content of not more than 6.5% w/w based on the weight of the active ingredient and at least one additional acceptable excipient from a pharmaceutical point of view.

further, the pharmaceutical composition may contain as an active ingredient Pramiracetam hydrate in which the water content is from 6.5% w/w to 11.5% w/w, preferably from 7.5% to 8 .7% w/w based on the weight of the active ingredient and at least one pharmaceutically acceptable excipient.

Pramiracetam hydrate is preferably in crystalline form. If the water content of the Pramiracetam hydrate is less than 6.5% w/w, the surface of the crystals must be treated with water to increase the water content to at least greater than 6.5% w/w and 11.5% w/w or less, preferably 7.5% and 8.7% w/w. Its technical effect is that the disintegration time of the tablet is shorter, i.e. 1 to 5 minutes. Also, another effect is that the compression forces required to achieve the same average tablet hardness decrease.

If the water content is below 6.5% w/w relative to the weight of the active ingredient, it is observed under the microscope that in the manufacturing/shipping/storage type a thin layer of anhydrous Pramiracetam forms on the surface of the Pramiracetam hydrate crystals (Figure 1 ). This can occur even if the relative humidity of the contact medium (air for example) is low.

Anhydrous Pramiracetam is a viscous liquid with a tendency to stick to stainless steel surfaces. To reduce the formation of the anhydrous layer on the Pramiracetam crystal surface, the addition of water was evaluated. Levels of 00%, 1.09% and 2.19% w/w of additional water increase based on the weight of active ingredient per tablet were evaluated. Preferably, the water was added in a high shear mixer at a low addition rate to allow uniform distribution of the water over all crystal surfaces.

The effect of water surface treatment on API was observed under a microscope. The result is visible in Figure 3 which shows the Pramiracetam hydrate crystal surface at two levels of surface treatment compared to the original crystal surface.

Furthermore, the present invention discloses a pharmaceutical composition comprising as an active ingredient Pramiracetam hydrate, further comprising at least one pharmaceutically acceptable excipient selected from the group consisting of a bulking agent, a disintegrating agent, a binder , an anti-stick, a sliding agent and a lubricating agent.

Examples of bulking agents include microcrystalline cellulose, silicified microcrystalline cellulose, lactose, calcium phosphate, starch, sugars (dextrose, maltose, sucrose, glucose, fructose), sugar alcohols (mannitol, maltitol, sorbitol, xylitol), maltodextrins. The most preferred filler is microcrystalline cellulose.

Examples of disintegrants include Crospovidone (crosslinked polyvinylpyrrolidone), Croscarmellose (crosslinked carboxymethyl cellulose), wheat, corn, rice or potato starch, sodium carboxymethyl starch, sodium starch glycolate, pregelatinized starch, L-HPC (lowly substituted hydroxypropyl cellulose) . The most preferred disintegrant is Crospovidone.

Examples of binders include Hydroxypropyl Methyl Cellulose, Povidone, Hydroxy Propyl Cellulose, Carboxymethyl Cellulose, Ethyl Cellulose, Methyl Cellulose, Hydroxyethyl Cellulose, Polyvinylpyrrolidone, Polyvinyl Alcohol, Polymers of Acrylic Acid and Its Salts, Vinylpyrrolidone-Vinyl Acetate Copolymers, Gelatin, Guar Gum, Pregelatinized Starch , alginates, xanthan. The preferred binder is Hydroxypropyl Methyl Cellulose.

Examples of anti-stick include talc, magnesium stearate, starch. The most preferred non-stick is talc.

Examples of glidants include colloidal silicon dioxide, starch, silicates. The most preferred glidant is colloidal silicon dioxide.

Examples of lubricants include magnesium stearate, calcium stearate, sodium stearate, stearic acid, hydrogenated vegetable oil, poly ethylene glycol, sodium benzoate, sodium lauryl sulfate. The most preferred lubricant is magnesium stearate.

In a preferred embodiment, the pharmaceutical composition according to the present invention is formulated in the form of a tablet.

In yet another preferred embodiment, the pharmaceutical composition comprises Pramiracetam hydrate with a water content greater than 6.5% w/w and 11.5% w/w or less, preferably 7.5% or more and 8.7% w/w or less based on the amount of Pramiracetam hydrate and at least one pharmaceutically acceptable excipient selected from: microcrystalline cellulose, crospovidone (cross-linked polyvinyl pyrrolidone), hypromellose (hydroxypropyl methyl cellulose), talc, colloidal silicon dioxide and magnesium stearate.

In a further aspect, the invention provides a process for the preparation of the pharmaceutical composition in which Pramiracetam hydrate with a specific water content of less than 6.5% w/w based on the weight of the active ingredient and optionally one or more pharmaceutical excipients, it is treated with water.

This thus provides a process for the preparation of the pharmaceutical composition, characterized in that Pramiracetam hydrate with a water content of less than 6.5 w/w relative to the total weight of Pramiracetam hydrate is treated with water until the water content of of Pramiracetam hydrate increases above 6.5% w/w calculated relative to the weight of the active ingredient, i.e. from 6.5% w/w to 11.5% w/w, preferably from 7.5% to 8, 7% w/w based on the weight of Pramiracetam hydrate using wet granulation and at least one pharmaceutically acceptable excipient.

in a preferred embodiment, the process for the preparation of the pharmaceutical composition according to the invention comprising the following steps:

a) Adding water to a Pramiracetam hydrate composition having less than 6.5% w/w relative to the total weight of the active ingredient until the water content of the Pramiracetam hydrate increases above 6.5% w/w calculated relative to to the weight of the active ingredient, i.e. from 6.5% w/w to 11.5% w/w, preferably from 7.5% to 8.7% w/w based on the total amount of the active ingredient using granulation wet,

b) Mixing the hydrated composition of step a) with at least one pharmaceutically acceptable excipient selected from the group consisting of a filler, disintegrant, binder, anti-adherent, slip agent and lubricant,

c) Compressing the mixture into tablets, and

d) optionally, compressing the tablet core.

In a preferred embodiment, the process for preparing the pharmaceutical composition of the invention is characterized in that the wet granulation is high shear granulation or spray granulation.

Such treatment is carried out by any type of wet granulation, for example high shear granulation (by spray or pour-in addition method) in a granulator, low shear granulation with higher spray granulation using a Fluidized Bed Processor, etc. . until the water content of the Pramiracetam hydrate increases above 6.5% w/w calculated relative to the weight of the active ingredient.

Pramiracetam hydrate wherein the water content is from 6.5% w/w to 11.5% w/w, preferably from 7.5% w/w to 8.7% w/w based on weight of the active ingredient is converted into a pharmaceutical formulation, preferably a tablet, by direct compression of a mixture containing Pramiracetam hydrate and excipients selected from bulking agent, disintegrating agent, binder, anti-adhesion agent, gliding agent and lubricating agent or Pramiracetam hydrate is granulated with at least one excipient and then converted into the desired pharmaceutical composition.

The water content of Pramiracetam hydrate is evaluated by the Karl Fischer method due to the low melting point of the active ingredient.

Surface treatment of Pramiracetam hydrate alone or in combination with excipients, wherein the water content is increased between 0.5% - 5% w/w (Corresponding to at least 3.2 - 32 mg water per tablet) to a target of 6.5 to 11.5% w/w based on the total weight of the active ingredient per tablet, (eg considering the molecular weights of Pramiracetam and Pramiracetam hydrate as 269.383 and 287.4 g/mol respectively), in any suitable granulation equipment has the following effects: the pharmaceutical composition obtained by the process disclosed in the present invention results in tablets with increased hardness. The addition of water to the composition results in increased compressibility of the mixture, as indicated by the decrease in the compression force required during the compression process to achieve the same core hardness using the same compression tool, which was indicative of tablet hardness, by adding water as a surface treatment in the manufacturing process of the pharmaceutical composition. It is also noted that the degree of sticking of API on machine parts (turret plate, force feed parts, punches) has been considerably reduced.

In another aspect, the present invention provides the pharmaceutical composition for use in therapy. In particular, the pharmaceutical composition is administered orally. More specifically, the disclosed pharmaceutical composition is used to treat memory and attention deficits due to aging or associated with neurodegenerative disorder and vascular dementia.

Water addition mechanism

1. The anhydrous layer contacts and adsorbs water and hydrates (Figure 2).

2. The layer adsorbs more water and through crystallization expands (increases volume by forming new networks).

3. The pressure inside the layer increases and stress cracks form in the surface layer.

4. Stress cracks increase in size with increasing water exposure and, by increasing depth in the crystal, expose more substance to water.

5. The process increases with exposure time and amount of water.

Impact of water addition on final formulation

Adding water to Pramiracetam hydrate triggers the transformation of the anhydrous adhesive layer on the surface of the crystal into a non-sticky hydrating layer. The amount of water added must be closely controlled as only the surface of the crystal needs to be treated. Too much water could introduce stress to the crystals which should be avoided. This is given by WKF of API and particle size distribution (PSD). Since only the surface of the crystals needs to be treated, the amount of water added will be strongly affected by the PSD value of the material. A higher PSD value of API means less crystal surface area and that will mean less water needed. We surprisingly found that 1.0 - 2.2% w/w of water based on the total weight of active ingredient per tablet was sufficient to transform most surfaces in this case.

With higher water addition content, stronger cracks form. It was observed that 0.5% - 5% w/w increase in water relative to active ingredient content per tablet was sufficient for surface treatment of Pramiracetam hydrate crystals, where the optimal additional level of surface water required for Pramiracetam hydrate was between 1.0 - 2.2% w/w relative to the Pramiracetam hydrate content per tablet. Once introduced into the dissolution medium, the water of the medium will move inside the tablet through a capillary phenomenon of MCC and reach the API crystals. The crystals will quickly take up water through the already formed gates (stress cracks) and disintegrate into smaller crystals with a higher surface area which will result in a higher and faster dissolution profile.

The process must be controlled. The amount of water should be sufficient to treat the API crystal surface and not affect the PSD value and crystal structure, so that the disintegration time and dissolution profile remain the same. It was observed that with higher water content, tablet hardness increases despite lower compressive strength.

EXAMPLES In the following, the invention will be disclosed by particular embodiments which should not be construed as limiting the invention in any way. Furthermore, the skilled person will anticipate that other variations may be made, all of which are within the scope of the invention.

Example 1 (Comparative):

Preparation of Pramiracetam tablets without additional treatment with water.

All raw materials and excipients according to Table 1 below were weighed. The required amount of API (Pramiracetam monohydrate) was ground through a suitable mill to the appropriate parameters. Talc and colloidal silicon dioxide were passed through appropriate size sieve, mixed with ground API. Microcrystalline cellulose, hypromellose and crospovidone were passed through a suitable sieve and mixed with the previous mixture. Magnesium stearate which has passed through a suitable sieve is added to the above mixture and lubricated with magnesium stearate for 10 minutes. The final mixture was compressed into tablet cores using elongated form tools to a hardness of 110-150 N and finally coated with the appropriate film coating slurry.

Table 1: Qualitative and quantitative composition details for Pramiracetam tablets as per example 1

raw material/ Excipients Function r mg/tablet % weight/core weight of tablet Core Pramiracetam* ³ (as theoretical Pramiracetam* hydrate) Active agent 600.00 (640.13) 60.00 (64,013) Water ^μ Agent of crystallization/hydration 0 0 Microcrystalline cellulose eo Filling agent 310.00 31.00 Crospovidone Agent of disintegration 10.00 1.00 Sucrose Binder 10.00 1.00 talcum anti-slip 30.00 3.00 Colloidal silicon dioxide Gliding agent 30.00 3.00 Magnesium stearate Lubricating agent 10.00 1.00 Compressed core weight- 1000.00 100.00 film cover f Polyvinyl alcohol polyethylene glycol and Polyvinyl alcohol copolymers Shell material > movie 16.50 1.65 Triethyl cipher 0.90 0.09 talcum 6.60 0.66 Titanium dioxide 6.00 0.60 Final compressed weight - 1030.00

^Standard amount of Pramiracetam (Std.) is based on 100% w/w test value content (based on dry matter) of API and NIL water content.

*The standard amount of Pramiracetam hydrate was related to the molecular weights of Pramiracetam and Pramiracetam hydrate as 269.383 and 287.4 g/mol respectively, “Microcrystalline cellulose was adjusted based on the actual amount of API taken.

io ///

Observations of example 1 (comparative):

API water by KF: 6.5 % w/w

Tablet core hardness: 127.50 N

Tablet disintegration time (Min'Sec"): 17'45" - 25'00"

Example 2:

Preparation of Pramiracetam tablets with 7 mg additional surface water (Which corresponds to 1.09% w/w of the theoretical amount of Pramiracetam per unit (Reference Batch No. PL060).

All raw materials and excipients according to Table 2 below were weighed. The required amount of Pramiracetam hydrate was transferred to a granulator-mixer vessel and pre-mixed at low paddle speed for 5 minutes. Water for hydration required for the batch was added to the appropriate granulation parameters. The hydrated material was discharged into a suitable container and ground using suitable equipment and parameters. The hydrated and ground pramiracetam was mixed with talc and colloidal silicon dioxide in a suitable mixing vessel for 15 minutes. Microcrystalline cellulose, hypromellose and crospovidone were separately passed through appropriate size sieves and added to the previous mixture and mixed for 15 minutes at appropriate speed.

Magnesium stearate passed through a suitable sieve was added to the above mixture and lubricated with magnesium stearate for 10 minutes. The final mixture was compressed into tablet cores using elongated shape tools to a target hardness of 110-150 N and finally coated with the appropriate film coating slurry.

Table 2: Qualitative and quantitative composition details for Pramiracetam tablets according to example 2

raw material/ Excipients Function f mg/tablet % weight/core weight of tablet Core Pramiracetam* ³ (as theoretical Pramiracetam* hydrate) Active agent 600.00 (640.13) 60.00 (64,013) Water ^μ Agent of 7.00 0.70

crystallization/hydration Microcrystalline cellulose 00 Filling agent 303.00 30,30 Crospovidone Agent of disintegration 10.00 1.00 Sucrose Binder 10.00 1.00 talcum anti-slip 30.00 3.00 Colloidal silicon dioxide Gliding agent 30.00 3.00 Magnesium stearate Lubricating agent 10.00 1.00 Compressed core weight- 1000.00 100.00 the film cover Polyvinyl alcohol polyethylene glycol and Polyvinyl alcohol copolymers The material of the film cover 16.50 1.65 Triethyl citrate 0.90 0.09 talcum 6.60 0.66 Titanium dioxide 6.00 0.60 Final compressed weight - 1030.00

^p Standard amount of Pramiracetam (Std.) is based on 100% w/w test value content (based on dry matter) of API and NIL water content.

'The standard amount of Pramiracetam hydrate was related to the molecular weights of Pramiracetam and Pramiracetam hydrate as 269.383 and 287.4 g/mol respectively, ^p What theoretically remains in the final product since no drying step is involved, after API wetting.

“Microcrystalline cellulose was adjusted based on the actual amount of API taken.

Example 2 observations:

Average water content of API water by KF before hydration: 6.465 % water content of API by KF after hydration: 7.18 % (average value)

Tablet core hardness: 122.90 N

Tablet disintegration time (Min'Sec"): 11Ό0" - 26'15"

Example 3:

Preparation of Pramiracetam tablets with 14 mg additional surface water (Which corresponds to 2.18% w/w relative to the theoretical amount of Pramiracetam per unit.)

All raw materials and excipients according to Table 3 below were weighed. The required amount of Pramiracetam hydrate was transferred to a granulator-mixer vessel and the API was pre-mixed at low paddle speed for 3 minutes. Water for hydration required for the batch was added to the appropriate granulation parameters. The hydrated material was discharged into a suitable container and mixed with previously sifted thal and colloidal silicon dioxide in a suitable mixer in the appropriate parameters and then ground using a mill and the appropriate parameters. Microcrystalline cellulose, hypromellose and crospovidone were added to the above mixture and mixed for 15 minutes at the appropriate speed. Magnesium stearate passed through a suitable sieve was added to the above mixture and lubricated with magnesium stearate for 10 minutes. The final mixture was compressed into tablet cores using elongated shape tools to a target hardness of 110-150 N and finally coated with the appropriate film coating slurry.

Table 3: Qualitative and quantitative composition details for tablets of

Pramiracetam according to example 3

raw material/ Excipients Function i mg/tablet % weight/core weight of tablet Core Pramiracetam ¹⁵ (as theoretical Pramiracetam hydrate*) Active agent 600.00 (640.13) 60.00 (64,013) Water ^μ Agent of crystallization/hydration 14.00 1.40 Microcrystalline cellulose Co. Filling agent 296.00 29.60 Crospovidone Agent of disintegration 10.00 1.00 Sucrose Binder 10.00 1.00

talcum anti-slip 30.00 3.00 Colloidal silicon dioxide Gliding agent 30.00 3.00 Magnesium stearate Lubricating agent 10.00 1.00 Compressed core weight- 1000.00 100.00 the film cover I Polyvinyl alcohol polyethylene glycol and Polyvinyl alcohol copolymers The material of the film cover 16.50 1.65 Triethyl cipher 0.90 0.09 talcum 6.60 0.66 Titanium dioxide 6.00 0.60 Final compressed weight - 1030.00

^Standard amount of Pramiracetam (Std.) was relative to the 100% w/w test value content (based on dry matter) of the API and NIL water content.

The standard amount of Pramiracetam hydrate was related to the molecular weights of Pramiracetam and Pramiracetam hydrate as 269.383 and 287.4 g/mol, respectively, ^p Amount theoretically remaining in the final product since no drying step is involved, after API wetting.

“Microcrystalline cellulose was adjusted based on the actual amount of API taken.

Example 3 observations:

Average water content of API by KF before hydration: 6.5% w/w API water content by KF after hydration: 8.03% w/w

Tablet core hardness: 123.10 N

Tablet disintegration time (Min'Sec"): 1'44" - 1'51"

Table 4: Comparative compression forces during the compression process and average tablet hardness of pooled tablet core samples from Examples 1-3

Parameter Example 1(PL065), with No water Example 2 (PL060A), with 7 mg of water per unit Example 3 (PL072), with 14 mg of water per unit Current strength of 1 8.2-12.4 kN 7.0-9.7kN 6.9-7.2 kN

compression Average hardness of tablets from pooled samples 127.50N 122.90 123..10

There was a decrease in the compression forces required to achieve the same average tablet hardness with increasing unit water content. This increase in compressibility of the blend, as shown by the decrease in compressive forces, was a clear indirect indication of the increase in hardness of the base tablets by increasing the water content of the composition.

COMPARATIVE DISSOLUTION PROFILE

Table 5: Comparative dissolution profile of Example 3 vs Pramistar

Time (min) Mean % Dissolved Drug (%RSD) Filmed tablet by Pramiracetam 600 mg Pramistar 600 mg film-coated tablet Example 3 Reference 10 100(1.7) 72 (4.8) 15 101 (1.0) 92 (3.5) 20 99 (1.2) 99 (1.4) 30 99 (1.4) 98 (1.0) 45 98.1 (1.1) 98 (0.8) 60 98 (0.8) 98 (0.9) Value of Similar* N/A

* Test and references cleared more than 85% after 15 minutes

Dissolution conditions: 900 mL, pH 1.2, 75 RPM, 37°C, paddle

STABILITY DATA

Table 6: Accelerated stability data for Pramiracetam 600 mg film-coated tablets (of example 2 & 3)

S. No. Test Acceptance limits PL 072 (Example 3) PL060A (Example 2) 1 month 3 months 1 appearance white to off-white, biconvex, elongated, partially indented on both sides. Respect Respect

2 Packaging aspect White Respect Respect 3 Average weight 978.5 - 1081.5 mg (1030 ±5%) 1031.6 1041.2 4 Water (via KF) NMT 8% 7.2 6.6 5 Identification Retention time The sample retention time for the main peak is similar to the standard retention time for the main peak Respect Respect UV Associated substances ( The sample spectrum is similar to the standard spectrum HPLC-UV) 6 Acid 2- (Oxopyrrolidin-1-yl) acetic, IMP29 NMT 0.5% <0.05 <0.05 Any unspecified impurity NMT 0.2% <0.05 <0.05 Total NMT 1.0% <0.05 <0.05 Dissolution 7 pH 1.2, after 45min NLT 85% (weight/weight) 99.3 98.8 8 Test for (HPLC-UV) 95.0 - 105.0% of what is declared 100.7 101.2

All the parameters investigated are within the specified limits without any significant tendency of degradation or change in the quality attributes of the medicinal product during the studied period in the studied composition of the packaging material.

Claims (11)

demand 1. Pharmaceutical composition comprising as an active ingredient Pramiracetam hydrate with a water content of more than 6.5% w/w based on the weight of the active ingredient and at least one pharmaceutically acceptable excipient. 2. Pharmaceutical composition according to claim 1 comprising as active ingredient Pramiracetam hydrate in which the water content is from 6.5% w/w to 11.5% w/w, preferably from 7.5% to at 8.7% weight/weight calculated relative to the weight of the active ingredient. 3. Pharmaceutical composition according to claims 1 and 2, wherein the at least one pharmaceutically acceptable excipient is selected from the group comprising a bulking agent, a disintegrating agent, a binder, an anti-adhesion agent, a slip and a lubricant. 4. Pharmaceutical composition according to claims 1-3, which is a solid composition to be administered orally, preferably a tablet. 5. Pharmaceutical composition according to claims 1-4, wherein the excipients are - filler selected from the group comprising microcrystalline cellulose, silified microcrystalline cellulose, lactose, calcium phosphate, starch, sugars (dextrose, maltose, sucrose, glucose, fructose), sugar alcohols (mannitol, maltitol, sorbitol, xylitol), maltodextrins ; - disintegrating agent selected from the group consisting of Crospovidone (cross-linked polyvinyl pyrrolidone), Croscarmellose (cross-linked carboxymethyl cellulose), wheat, corn, rice or potato starch, sodium carboxymethyl starch, sodium starch glycolate, pregelatinized starch, L-HPC (hydroxypropyl weakly substituted cellulose); - binder selected from the group comprising Hydroxypropyl methyl cellulose, Povidone, Hydroxy propyl cellulose, carboxymethyl cellulose, ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, polymers of acrylic acid and its salts, vinylpyrrolidone-vinyl acetate copolymers, gelatin, guar gum , pregelatinized starch, alginates, xanthan; - anti-adherent selected from the group comprising Talc, magnesium stearate, starch; - slip agent selected from the group comprising colloidal silicon dioxide, starch, silicates; - lubricating agent selected from the group comprising magnesium stearate, calcium stearate, sodium stearate, stearic acid, hydrogenated vegetable oil, poly ethylene glycol, sodium benzoate, sodium lauryl sulfate. 6. Pharmaceutical composition according to claim 5 in which the excipients are selected from: - microcrystalline cellulose - Crospovidone (cross-linked polyvinyl pyrrolidone) - Hypromellose (hydroxypropyl methyl cellulose) Talc - colloidal silicon dioxide, and » - Magnesium stearate. 7. Process for the preparation of the pharmaceutical composition according to claims 1 to 6, characterized in that the _Pramiracetam hydrate with a water content of less than 6.5% w/w relative to the total weight of the active ingredient is treated with water until the water content of the Pramiracetam hydrate increases above 6.5% w/w calculated relative to the weight of the active ingredient, i.e. from 6.5% w/w to 11.5% w/w, preferably from 7, 5% to 8.7% w/w based on the weight of the active ingredient using wet granulation to obtain a hydrated composition which is subsequently mixed with at least one pharmaceutically acceptable excipient. 8. Process for the preparation of the pharmaceutical composition according to claim 7, characterized in that the wet granulation is high shear granulation or spray granulation. 9. Process for the preparation of the pharmaceutical composition according to claims 7-8 comprising the following steps: a) Adding water to a Pramiracetam hydrate composition having less than 6.5% w/w relative to the total weight of the active ingredient until the water content of the Pramiracetam hydrate increases above 6.5% w/w calculated relative to to the weight of the active ingredient, i.e. from 6.5% w/w to 11.5% w/w, preferably from 7.5% to 8.7% w/w based on the total weight of the active ingredient using granulation wet, b) Mixing the hydrated composition of step a) with at least one pharmaceutically acceptable excipient selected from the group consisting of a filler, disintegrant, binder, anti-adherent, slip agent and lubricant, c) Compressing the mixture into tablets, and d) optionally, coating the tablet core. 11. Pharmaceutical composition according to claims 1 to 6 for use in the treatment of memory and attention deficit. I I 12. A pharmaceutical composition according to claim 11 wherein said pharmaceutical composition is administered orally.