CLIAMS:We Claim:-

1. A zolpidem composition , comprising:
zolpidem tartrate and polacrillin potassium in a weight ratio of 1:8.

2. The zolpidem composition of claim 1, further comprising pharmaburst B2, lactose monohydrate, colloidal silicon dioxide anhydrous, a sweetener, a flavorant, and magnesium stearate.

3. The zolpidem composition of claim 2, wherein the sweetener is aspartame.

4. The zolpidem composition of claim 2, wherein the flavorant is Flavor-Black Current.

5. The zolpidem composition of claim 1, wherein the zolpidem tartrate and polacrillin potassium are physically mixed for about 60 minutes using a rotating blender.

6. The zolpidem composition of claim 1, wherein a sublingual oral disintegrating tablet of the zolpidem composition comprises 5 milligrams of zolpidem tartrate and 40 milligrams of polacrillin potassium.

7. The zolpidem composition of claim 1, wherein a sublingual oral disintegrating tablet of the zolpidem composition comprises 10 milligrams of zolpidem tartrate and 80 milligrams of polacrillin potassium.

8. A process for preparation of a zolpidem composition, comprising:

mixing zolpidem tartrate and polacrillin potassium in a weight ratio of 1:8 to form a taste masked dry mix;
mixing the pharmaburst B2, lactose monohydrate, colloidal silicon dioxide anhydrous, a sweetener, and a flavorant to form a flavor blend;
blending of the taste masked dry mix and the flavor blend to form an intermediate blend;
mixing of intermediate blend with magnesium stearate to form ready to compress granules of the zolpidem composition.

9. The process of claim 8, wherein the ready to compress granules of the zolpidem composition are compressed to form a sublingual oral disintegrating tablet.

10. The process of claim 9, wherein a sublingual oral disintegrating tablet of the zolpidem composition comprises 5 milligrams of zolpidem tartrate and 40 milligrams of polacrillin potassium.

11. The process of claim 9, wherein a sublingual oral disintegrating tablet of the zolpidem composition comprises 10 milligrams of zolpidem tartrate and 80 milligrams of polacrillin potassium.
,TagSPECI:ZOLPIDEM COMPOSITION AND PROCESS FOR PREPARING THE SAME

FIELD OF THE INVENTION

[0001] The present invention relates to zolpidem compositions and process for preparing the same.

BACKGROUND OF THE INVENTION
[0001] Zolpidem is a sedative that is used in the management of insomnia. It has been demonstrated to reduce sleep latency, increase sleep duration, and reduce night time awakenings. Zolpidem tablets and medications have been available for a long time; however the disintegration of conventional tablets is much slower resulting in decreased efficacy of the medicine. Further, due to the bitter taste of the conventional tablets, patients may have problems, particularly, elderly, patients with an impaired swallowing function, or patients with decreased saliva production. Accordingly, the oral intake of conventional tablets are a cumbersome process.
[0002] Also, orally disintegrating tablets (ODTs) are available. ODTs differ from conventional tablets in that they are designed to be dissolved/disintegrated in an oral cavity rather than swallowed whole. Accordingly, ODTs have been developed such that the same medicine can be orally administered in a simple and effective manner to children, adults and people with impaired swallowing function and similar conditions. Even a patient who is not suffering from any swallowing limitation will find it much easier to take an ODT as compared to a conventional tablet. An additional reason to use an orally disintegrating tablet is the convenience of a tablet that can be taken without water.
[0003] In view of ease of administration, the ODTs have a rapid disintegration rate as compared to conventional tablets. However, rapid disintegration properties and high tablet hardness are generally contradicting properties, and therefore ODTs cause chips and cracks of the tablets when divided because of insufficient tablet hardness and high friability. Due to high disintegration and low hardness, even the cracking or disintegration problems are faced in the course of production and/or distribution.
[0004] However, existing zolpidem ODT uses effervescent technology for taste masking. Further, also uses wet granulation method using ion exchange resins for taste masking. As used herein ion exchange resins are used for taste masking of various drugs by using wet granulation technique, wherein resins and drugs forms complex in presents of water/ solvent.
[0005] Also, preparation of the conventional taste masked zolpidem compositions requires several steps and requires use of one or more muco adhesive agents. Due to these problems the process for manufacturing a taste masked zolpidem compositions becomes time taking and complex.
[0006] Accordingly, what is required is a zolpidem compositions that has excellent disintegration and dissolution properties. Also, what is required is a taste masked zolpidem composition that can be easily prepared and administered. Further, what is required is a preparation process for zolpidem compositions that is simple, has uniformity reliability, and is time efficient.

SUMMARY OF THE INVENTION

[0007] In one aspect, the present invention provides zolpidem composition, comprising zolpidem tartrate and polacrillin potassium in a weight ratio of 1:8. The zolpidem composition further comprises pharmaburst B2, lactose monohydrate, colloidal silicon dioxide anhydrous, a sweetener, a flavorant, and magnesium stearate.
[0008] In another aspect, the present invention provides a process for preparation of a zolpidem composition. The process comprises: mixing zolpidem tartrate and polacrillin potassium in a weight ratio of 1:8 to form a taste masked dry mix; mixing the pharmaburst B2, lactose monohydrate, colloidal silicon dioxide anhydrous, a sweetener, and a flavorant to form a flavor blend; blending of the taste masked dry mix and the flavor blend to form an intermediate blend; mixing of intermediate blend with magnesium stearate to form ready to compress granules of the zolpidem composition; and compressing the ready to compress granules of the zolpidem composition to form a sublingual oral disintegrating tablet..

BRIEF DESCRIPTION OF THE DRAWINGS

[0009] The advantages and features of the present invention will become better understood with reference to the following detailed description and claims taken in conjunction with the accompanying drawing, in which:
[0010] FIG. 1 illustrates a process flow for preparation of a zolpidem composition, in accordance with an exemplary embodiment of the present invention; and
[0011] FIG. 2 illustrates details of preparation of taste masked dry mix of process of FIG. 1;
[0012] FIG. 3 illustrates details of preparation of flavor blend of process of FIG. 1;
[0013] FIG. 4 illustrates details of preparation of intermediate blend of process of FIG. 1;
[0014] FIG. 5 illustrates details of preparation of granules of process of FIG. 1;
[0015] FIG. 6 illustrates details of compression of granules of process of FIG. 1 to form sublingual oral disintegrating tablet; and
[0016] FIG. 7 illustrates details of packing of sublingual oral disintegrating tablet.

DETAILED DESCRIPTION OF THE INVENTION
[0017] The exemplary embodiments described herein detail for illustrative purposes are subject to many variations in structure and design. It should be emphasized, however, that the present invention is not limited to a zolpidem composition and process for preparing the same, as shown and described. It is understood that various omissions and substitutions of equivalents are contemplated as circumstances may suggest or render expedient, but these are intended to cover the application or implementation without departing from the spirit or scope of the claims of the present invention. Also, it is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting.

[0018] The use of terms “including,” “comprising,” or “having” and variations thereof herein is meant to encompass the items listed thereafter and equivalents thereof as well as additional items. Further, the terms, “a” and “an” herein do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced item.

[0019] The present invention provides a zolpidem composition and a process for preparing the same. The zolpidem composition of the present invention has a taste masking achieved by only physical mixing of drug with an ion-exchange resin. As illustrated herein and described below, the preparation of the taste masked zolpidem composition requires fewer steps as compared to conventional taste masked zolpidem compositions. Also, the preparation process of the present invention employs direct compressible excipients without the use of any muco adhesive agents.
[0020] The zolpidem composition is further compressed using direct compression techniques and available as sublingual oral disintegrating tablet (ODT). Such compositions and formed ODTs are low dosage (5 milligrams, 10 milligrams) formulations. The sublingual ODT has excellent dissolution and disintegration properties and thus very quickly disperses in mouth without any need of water. Such ODTs are very handy for geriatric patients, patients with mental disabilities, and patients with impaired swallowing function.
[0021] The present invention provides a zolpidem composition comprising: zolpidem tartrate (drug) and polacrillin potassium (ion-exchange resin) in a weight ratio of 1:8.
[0022] The zolpidem composition further comprises Pharmaburst B2, lactose monohydrate, colloidal silicon dioxide anhydrous, a sweetener, a flavorant, and magnesium stearate.
[0023] As used herein, zolpidem tartrate is widely used to treat sleeping problems. Zolpidem tartrate is a white to off-white crystalline powder that is sparingly soluble in water, alcohol, and propylene glycol. As used in the present invention, zolpidem tartrate is obtained from Aarti Drugs Ltd.
[0024] Polacrilin potassium is the ion-exchange resin employed in the present invention. As used herein, the polacrilin potassium is an ion exchange resin used in oral pharmaceutical formulations as a tablet disintegrant. It is a weakly acidic cation exchange resin. Chemically, it is a partial potassium salt of a copolymer of methacrylic acid with divinyl benzene. As used in the present invention, polacrilin potassium is obtained from Corel Pharma Chem under the trade name Kyron T -134.
[0025] Pharmaburst B2 is employed in the present invention as a co-process excipient (diluent) for direct compression technique. As used herein, the pharmaburst B2 is used by the nutritional and pharmaceutical industry in the production of "quick dissolve" tablets. Pharmaburst B2 consists of 85 percent mannitol, 10 percent polyplasdone, 5 percent sorbitol (a sweetener), and less than one percent syloid. As used in the present invention, pharmaburst B2 is obtained from SPI Pharma.
[0026] Further, as used herein, lactose monohydrate as a second diluent is used. Lactose monohydrate is milk sugar (Chemically C12H22O11). It is a disaccharide composed of one galactose and one glucose molecule. It is used to help form tablets because it has excellent compressibility properties. As used in the present invention, lactose monohydrate may be obtained from one of DMV, Fonterra Excipients and DFE Pharma. For example, lactose monohydrate is obtained from DFE Pharma under the Trade Name Supertab 30® GR.
[0027] Colloidal silicon dioxide anhydrous is employed in the present invention as a glidant. As a glidant, colloidal silicon dioxide anhydrous serves as a material for improving powder flow since colloidal silicon dioxide is inert and doesn't dissolve in water. As used herein the colloidal silicon dioxide anhydrous refers to a fumed silica prepared by vapour-phase hydrolysis of a silicon compound, such as silicon tetrachloride. The product itself is usually a submicron, fluffy, light, loose, bluish-white, odourless and tasteless amorphous powder which is commercially available from a number of sources, including Cabot Corporation (under the trade name Cab-O-Sil®); Degussa, Inc. (under the trade name Aerosil®); Huber Engineered Materials (Huber GL100 and GL200®); Wacker (Wacker HDK ®); and E.I. DuPont & Co. As used in the present invention, colloidal silicon dioxide anhydrous is obtained from Evonik. Colloidal silicon dioxide is also commonly known as Aerosil, colloidal silica, fumed silica, light anhydrous silicic acid, silicic anhydride, and silicon dioxide fumed, among others. In one embodiment, the colloidal silicon dioxide used is Aerosil 200. A variety of commercial grades of colloidal silicon dioxide are produced by varying the manufacturing.
[0028] As used herein, the sweeteners can include aspartame, saccharin sodium, dipotassium glycyrrhizinate, stevia, thaumatin, acesulfame K, sucralose, and combinations of the foregoing. In one embodiment, the sweetener is aspartame. Aspartame is an artificial, non-saccharine sweetener used as a sugar substitute in some foods and beverages. Aspartame is a methyl ester of the aspartic acid/phenylalanine dipeptide. As used in the present invention, the aspartame is obtained from Nutra sweets.
[0029] The flavoring agents that can be used include natural and artificial flavors. These flavors may be one or more of synthetic flavor oils and flavoring aromatics, and/or oils, oleo resins and extracts derived from plants, leaves, flowers, fruits, etc., and combinations thereof. Representative flavor oils include: spearmint oil, cinnamon oil, peppermint oil, clove oil, bay oil, thyme oil, cedar leaf oil, oil of nutmeg, oil of sage, and oil of bitter almonds. Also useful are artificial, natural or synthetic fruit flavors such as vanilla, chocolate, coffee, cocoa and citrus oil, including lemon, orange, grape, lime and grapefruit and fruit essences including apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot and so forth. These flavorings can be used individually or in admixture. Commonly used flavors also include mints such as peppermint, artificial vanilla, cinnamon derivatives, and various fruit flavors, whether employed individually or in admixture. Flavorings such as aldehydes and esters including cinnamyl acetate, cinnamaldehyde, citral, diethylacetal, dihydrocarvyl acetate, eugenyl formate, p-methylanisole, and so forth may also be used. In one embodiment, the flavorant is Flavor- Black Current. As used in the present invention, the Flavor- Black Current is obtained from Firmenich. The Flavor- Black Current provides a good mouth feel.
[0030] Magnesium Stearate is employed in the present invention as a lubricant. Lubricants can be added to granules both during the final mixing phase before compression and during granulation. Among the traditional solid lubricants, calcium, magnesium, and zinc salts of stearic acid, partially hydrogenated vegetable oils, polyethylene glycols, polyoxyethylene monostearate, talc, sodium benzoate, sodium laurylsulfate, magnesium oxide can be used. In one embodiment lubricant is used in the blending applications for anti-adherent activity (i.e., prevent sticking to punch faces and die walls), glidant activity (i.e., improve the flowability of the powder or granules), and lubricant activity (i.e., reduce friction, transfer heat, and prevent corrosion during the process).
[0031] As used herein, magnesium stearate refers to a white powdered substance having the chemical formula Mg(C18H35O2)2. It is a salt containing two equivalents of stearate (the anion of stearic acid) and one magnesium cation (Mg2+). Magnesium stearate is used herein to serve as a lubricating medium for the composition. Magnesium stearate prevents ingredients from sticking to manufacturing equipment during the compression of chemical powders into solid tablets. Magnesium stearate has advantages over other lubricants because of its high melting temperature, high lubricity at a low concentration, large covering potential, general acceptance as safe, nontoxicity, and its excellent stability profile. As used in the present invention, the magnesium stearate is obtained from Ferro Corporation.
[0032] Further, the present invention provides a process for preparation of the zolpidem composition as described above (hereinafter referred to as process). The process employs a physical mixing, blending, lubricating, tablet compression and packing to obtain the zolpidem sublingual ODT.

[0033] The preparation process 100 is described herein with reference to FIGS. 1-6; and packing of the zolpidem sublingual ODT is described herein with reference to FIG. 7. In FIG. 1, the primary process steps are illustrated, while in FIGS. 2, 3, 4, 5, and 6 illustrated are the details of steps in FIG. 1.

[0034] Referring to FIG. 1, at step 102, the process 100 initiates by mixing zolpidem tartrate (drug) and polacrillin potassium (ion-exchange resin) in a weight ratio of 1:8 to form a taste masked dry mix. At step 104, the process 100 comprises mixing the pharmaburst B2, lactose monohydrate, colloidal silicon dioxide anhydrous, a sweetener, and a flavorant to form a flavor blend. At step 106, the process 100 comprises blending of the taste masked dry mix and the flavor blend to form an intermediate blend. At step 108, the process 100 comprises mixing of intermediate blend with magnesium stearate to form a ready to compress granules of the zolpidem composition. At step 110, the ready to compress granules are compressed to form a sublingual ODT.
[0035] In one embodiment, at step 102, the zolpidem tartrate and polacrillin potassium are physically mixed for about 60 minutes using a rotating blender. Now, referring to FIG. 2, illustrated are the details of the dry mixing/physical mixing process of step 102 of FIG. 1 to form a taste masked dry mix through representations 202, 204, 206 and 208. At step 202, zolpidem tartrate is physically mixed with polacrillin potassium. At 204, the mix formed at 202 is sieved/sifted through a 36 mesh fitted with vibratory sifter to form a sifted mass of zolpidem tartrate and polacrillin potassium. Further, at 206, the sifted mass of zolpidem tartrate and polacrillin potassium are loaded and blended in the conta blender (rotating blender) to form the taste masked dry mix. In one embodiment, at 206 the blending is done in 120 litre conta blender for 60 minutes at the blender speed of 8 revolutions per minute (RPM). Thereafter, at 208, the taste masked dry mix is unloaded in a double poly bag lined HDPE container and labeled properly from inside and outside of container. Although a mesh screen of particular dimension is mentioned above, it will be evident to a person skilled in the art to use mesh sieves of varying dimensions for obvious variations. Also, although a particular volume of the blender and mixing time is mentioned, it will be evident to a person skilled in the art to use blender of varying dimensions and time for obvious variations.
[0036] Now, referring to FIG. 3, illustrated are the details of the step 104 of FIG. 1 to form a flavor blend through representations 302, 304, 306 and 308. At step 302, Pharmaburst B2, lactose monohydrate, colloidal silicon dioxide anhydrous, the sweetener and the flavorant are mixed with each other. At 304, the mix formed at 302 is sieved/sifted through a 36 mesh fitted with vibratory sifter to form a sifted flavor blend. Further, at 306, the sifted flavor blend is loaded and blended in the conta blender to form flavor blend. In one embodiment, the blending is done in 120 litre conta blender for 20 minutes at the blender speed of 8 RPM. Thereafter, at 308, 50% of flavor blend is unloaded in a double poly bag lined HDPE container and labeled properly from inside and outside of container. Although a mesh screen of particular dimension is mentioned above, it will be evident to a person skilled in the art to use mesh sieves of varying dimensions for obvious variations. Also, although a particular volume of the blender and mixing time is mentioned, it will be evident to a person skilled in the art to use blender of varying dimensions and time for obvious variations.

[0037] Now, referring to FIG. 4, illustrated are the details of the step 106 of FIG. 1 to form an intermediate blend through representations 402 and 404. Specifically, referring to 402 and 404 of FIG. 4, the intermediate blend is formed at 402 by blending of taste masked dry mix and flavor blend. More specifically, the first step comprises adding taste masked dry mix to 50% of the flavor blend in a contra blender bin. In a second step, the remaining 50% of the flavor blend is added. In one embodiment, at 404, the blending is done in 120 litre conta blender for 30 minutes at the blender speed of 8 RPM. Although a particular volume of the blender and mixing time is mentioned, it will be evident to a person skilled in the art to use blender of varying dimensions and time for obvious variations.
[0038] Now, referring to FIG. 5, illustrated are the details of the step 108 of FIG. 1 to form ready to compress granules of the zolpidem composition through representations 502, 504, and 506. At 502, magnesium stearate (as a lubricant) is added to the intermediate blend. At 504, the sieving/sifting is done through a 40 mesh fitted with vibratory sifter to form a sifted ready to compress granules. Further, the sifted ready to compress granules is blended with intermediate blend as illustrated at 506 in the conta blender to form ready to compress granules. At 506, the blending is done in 120 litre conta blender for 5 minutes at the blender speed of 8 RPM. Although a mesh screen of particular dimension is mentioned above, it will be evident to a person skilled in the art to use mesh sieves of varying dimensions for obvious variations. Also, although a particular volume of the blender and mixing time is mentioned, it will be evident to a person skilled in the art to use blender of varying dimensions and time for obvious variations.
[0039] Now, referring to FIG. 6, illustrated are the details of the step 110 of FIG. 1 to compress the granules through representations 602, 604, and 606. At 602, 604, 606 the compression is performed using rotary tablet compression machine at a speed of about 25 revolutions per minute for form bulk tablet. Further, the compressing parameters for compressing the ready to compressed granules having different zolpidem compositions are described in the examples below.
[0040] The process may further comprise packing the zolpidem compositions. Referring to FIG. 7, at representations 704 and 706 the details of the packing are mentioned. The packaging will be performed in Aluminum – Aluminium blister pack machine with speed of about 20 + 5 strokes per minute and sealing heater temperature of about 190 + 20 degree centigrades.
[0041] The description of the zolpidem compositions of the present invention is further illustrated by the following non-limiting examples. However, a person skilled in the art would recognize that the examples described herein intended only to illustrate, not limit, the scope of the present invention.

EXAMPLE 1
[0042] In Example 1, a process for preparing a 5 milligram (mg) zolpidem compositions is described. The process for preparing zolpidem compositions of the present invention was initiated by physically mixing 5mg of zolpidem tartrate with 40 mg of polacrillin potassium. The mix so formed is sieved/sifted through a 36 mesh fitted with vibratory sifter to form a sifted mass of zolpidem tartrate and polacrillin potassium. Further, the sifted mass of zolpidem tartrate and polacrillin potassium are loaded and blended in the conta blender (rotating blender) to form the taste masked dry mix. The blending is done in 120 litre conta blender for 60 minutes at the blender speed of 8 revolutions per minute (RPM). Thereafter, the taste masked dry mix is unloaded in a double poly bag lined HDPE container and labeled properly from inside and outside of container
[0043] Next, the flavor blend is prepared by mixing 85.75 mg of Pharmaburst B2, 13 mg of lactose monohydrate, 1.5 mg of colloidal silicon dioxide anhydrous, 2.5 mg of sweetener and 0.75 mg of flavorant with each other. The mix so formed at is sieved/sifted through a 36 mesh fitted with vibratory sifter to form a sifted flavor blend. Further, the sifted flavor blend is loaded and blended in the conta blender to form flavor blend. In one embodiment, the blending is done in 120 litre conta blender for 20 minutes at the blender speed of 8 RPM. Thereafter, 50% of flavor blend is unloaded in a double poly bag lined HDPE container and labeled properly from inside and outside of container.
[0044] Next, the Intermediate blend is formed by blending of taste masked dry mix and flavor blend. More specifically, the first step comprises adding dry mix to 50% of the flavor blend in a contra blender bin. In a second step, the remaining 50% of the flavor blend is added. The blending is done in 120 litre conta blender for 30 minutes at the blender speed of 8 RPM.
[0045] Thereafter, ready to compress granules is prepared by adding 1.5 mg of magnesium stearate (as a lubricant) to the intermediate blend. The sieving/sifting is done through a 40 mesh fitted with vibratory sifter to form a sifted ready to compress granules. Further, the sifted ready to compress granules is blended with intermediate blend as illustrated in the conta blender to form ready to compress granules. The blending is done in 120 litre conta blender for 5 minutes at the blender speed of 8 RPM.
[0046] Finally, 5 mg of zolpidem composition is formed by compressing the ready to compress granules. The compression is performed using rotary tablet compression machine at a speed of about 25 revolutions per minute. Specifically, the ready to compress granules are compressed from 3.4 using rotatory tablet compression machine fitted with 7.0 mm round flat bevelled punches and dies using the tablet compression parameters described in the below Table 1. Also, referring to Table 1 below illustrated below are the parameters by which the lubricated pre- compression composition is compressed:-

TABLE 1

Sr. No. PARAMETERS STANDARD LIMITS
1 Appearance White to off white, Round, flat, bevelled edged tablets plain on both the surfaces having characteristic odour.
2 Punch description 7 mm round flat bevelled edge punches plain on both the surfaces with corresponding dies
3 Weight of 20 tablets 3.0 g 3.00 g ± 3% (2.91 – 3.09 g)
4 Individual tablet weight (n = 20) 150 mg 150 mg ± 5% (143 – 158 mg)
5 Thickness (n = 5) 3.2 mm 3.2 mm ± 0.3 mm (2.9 – 3.5 mm)
6 Diameter (n = 5) 7.0 mm 7 mm ± 0.3 mm (6.7 – 7.3 mm)
7 Hardness (n = 5) 35 N 20 N – 50 N
8 Disintegration time NMT 60 seconds using water at 370C ± 2°C without disc NMT 60 seconds using water at 370C ± 2°C without disc
9 Friability NMT 1.0 % NMT 1.0 %

[0047] Although particular compression parameters are mentioned above, it will be evident to a person skilled in the art to modify parameters based on obvious variations.
[0048] Further, In Table 2 below, the different ingredients of the zolpidem composition are depicted along with details on pharmacopeial reference, the vendor from whom the ingredient was obtained, percent by weight of each ingredient and weight in mg of each ingredient. In tables below “(a)” denotes quantity of API shall be considered based on moisture content and % assay potency and “(b)” denotes quantity of API shall be adjusted against quantity of polacrilin potassium (kyron T -134)
TABLE 2
Ingredients Manufacturer Quality Referential % w/w mg/
tab

Taste masked dry mix
Zolpidem Tartrate (a) (Particle size D90 = 50µ ) Aarti drugs Ltd Ph.Eur 3.33 5.0
Polacrilin Potassium (b) (Kyron T -134) Corel Pharma Chem USP 26.66 40.0
Flavor Blend
Pharmaburst B2 SPI Pharma In-house 57.17 85.75
Lactose monohydrate (Supertab 30 GR) DMV, Fonterra Excipients/DFE Pharma Ph.Eur 8.67 13.0
Aspartame Nutrasweets Ph.Eur 1.67 2.5
Colloidal silicon dioxide anhydrous
(Aerosil 200) Evonik Ph.Eur 1.0 1.5
Flavor- Black Current
(502009 AP0551) Firmenich In-house 0.5 0.75
Lubrication
Magnesium stearate Ferro Corporation Ph.Eur 1.0 1.5
Total 100.0 150.0

[0049] Specifically, the process and composition details described in Example 1 and Table 2 is used for preparing 5 mg zolpidem compositions. Multiple experiments were conducted to form 5 mg zolpidem compositions, i.e, to form zolpidem compositions comprising 5 mg of zolpidem Tartrate. For example, experiment for batches 1, 2 and 3 were conducted for forming 5 mg zolpidem compositions. It was found all batches resulted in substantially the same content indicating consistency in uniformity of content that is desirable for lower dosage compositions of 5 mg. Such properties for the different batches are illustrated in Tables below. Table 3 below illustrates the batch quantity for 2, 00,000 tablets in kilograms (kg). Table 4 below illustrates the analytical result of taste masked dry mix solution for different batches. Table 5 below illustrates the analytical result of unlubricated granules. In Tables 4 and 5, it can be concluded, blend uniformity test of Zolpidem Tartrate for all three batches shows that the drug content at all the ten points are within the specification and % RSD value less than 5, there by demonstrating adequate distribution of the drug. Table 6 illustrates the analytical result of lubricated granules. In Table 6, it can be concluded, assay and blend uniformity test for Zolpidem tartrate content was within the specification indicating uniform distribution of drug and also uniform distribution of particle size was observed in all three batches. Table 7 illustrates the analytical result of bulk tablets. In Table 7, it can be concluded, physical parameters and analytical results (Content of uniformity, Assay, dissolution, RS and Micro) of Zolpidem Tartrate were found within the specification for all three batches. Thus it concludes that direct compression process is suitable and reproducible for manufacturing of Zolpidem Tartrate sublingual orally disintegrating tablets. Table 8 illustrates the analytical result of pack tablets. In Table 8, it can be concluded, tablets were pack in Alu – Alu blister pack. Samples analysis results were complies with physical, chemical and Microbial limit tests specifications.

TABLE 3

Ingredients Batch Quantity for 2,00,000 tablets (kg)
1 2 3
Zolpidem Tartrate (a) (Particle size D90 = 50µ ) 1.02(a) 1.03(a) 1.00(a)
Polacrilin Potassium (b) (Kyron T -134) 7.98(b) 7.97(b) 8.00(b)
Flavor Blend
Pharmaburst B2 17.15 17.15 17.15
Lactose monohydrate (Supertab 30 GR) 2.60 2.60 2.60
Aspartame 0.50 0.50 0.50
Colloidal silicon dioxide anhydrous
(Aerosil 200) 0.30 0.30 0.30
Flavor- Black Current
(502009 AP0551) 0.15 0.15 0.15
Lubrication
Magnesium stearate 0.30 0.30 0.30
Total 30.00 30.00 30.00

TABLE 4
Taste masked dry mix Yield 1 2 3
Theoretical yield 8.98 kg 8.98 kg 8.98 kg
Practical yield in kg 8.96 kg 8.96 kg 8.98 kg
% Practical yield 99.77 % 99.77 % 100.0%

TABLE 5

Tests 1 2 3
Appearance White to off white granules having characteristic odour White to off white granules having characteristic odour White to off white granules having characteristic odour
Blend uniformity:
33.67 mg/g
30.30 to 37.04 mg/g
(90 .0 % to 110.0% of L.C)
RSD: Not more than 5.0%
Min: 96.0 %
Max: 100.8 %
Avg: 98.8 %
RSD: 1.5% Min: 97.4 %
Max: 109.0 %
Avg: 100.2%
RSD: 3.2 % Min: 97.8 %
Max: 101.6 %
Avg: 99.5 %
RSD: 1.4%

TABLE 6
Tests 1 2 3
Appearance White to off white granules having characteristic odour White to off white granules having characteristic odour White to off white granules having characteristic odour
Loss on drying:
Not more than 5% 1.89 % 2.19 % 2.07 %
Assay:
33.33 mg/g
31.66 – 35.0 mg/g
(95 – 105% of L.C) 33.81 mg/gm
101.4 % 33.53 mg/gm
100.6 % 33.15 mg/gm
99.4 %
Particle size distribution:
Not less than 95% particles passes through 500µ 20 # = 0.12 %
35#= 0.40 %
40# = 0.60 %
50 # = 1.85 %
60 # = 4.00 %
80# = 11.16 %
100 # = 31.27 %
120 # = 38.71 %
Below 120# = 99.22 % 20 # = 0.12 %
35#= 0.44 %
40# = 0.72 %
50 # = 2.03 %
60 # = 4.24 %
80# = 11.10 %
100 # = 31.18 %
120 # = 38.57 %
Below 120# = 97.09 % 20 # = 0.10 %
35#= 0.28 %
40# = 0.84 %
50 # = 2.64%
60 # = 5.02 %
80# = 25.25 %
100 # = 43.73 %
120 # = 56.17 %
Below 120# = 99.96 %
Bulk density 0.63 gm/ml 0.61 gm/ml 0.61 gm/ml
Tapped density 0.85 gm/ml 0.82 gm/ml 0.83 gm/ml
Blend uniformity:
33.33 mg/g
30.00 – 36.66 mg/g
(90.0 % – 110.0 % of L.C)
RSD: Not more than 5.0 % Min: 98.0 %
Max: 101.8 %
Avg: 100.8 %
RSD: 1.2% Min: 97.4 %
Max: 101.2 %
Avg: 99.4 %
RSD: 1.2% Min: 97.1 %
Max: 101.9 %
Avg: 99.0 %
RSD: 1.8%
Related substance:
ND

ND

ND

Zolpidem Impurity A – Not more than 0.20 %
Each unknown impurities –
Not more than 0.20% BDL BDL BDL
Total impurities – Not more than 0.50% BDL BDL BDL
Microbial Limit Test :
Total aerobic microbial unit : NMT 1000 cfu/g Less than 10 CFU/g Less than 10 CFU/g Less than 10 CFU/g
Total yeast and mold count : NMT 100 cfu/g Less than 10 CFU/g Less than 10 CFU/g Less than 10 CFU/g
Following pathogens should be absent in 1 g:
Escherichia coli Absent in 1 g Absent in 1 g Absent in 1 g
staphylococcus aureus Absent in 1 g Absent in 1 g Absent in 1 g
Pseudomonas aeruginosa Absent in 1 g Absent in 1 g Absent in 1 g
salmonella species should be absent in 10 g. Absent in 10 g Absent in 10 g Absent in 10 g
Theoretical weight of granules
Quantity of granules obtained 29.42 kg 29.44 kg 29.36 kg
Yield of granules 99.80 % 99.87 % 99.73 %
Process Loss 0.06 kg 0.04 kg 0.08 kg

TABLE 7
Tests 1 2 3
Description White to off white, round, flat, bevelled edged tablets plain on both the surfaces having characteristic odour White to off white, round, flat, bevelled edged tablets plain on both the surfaces having characteristic odour White to off white, round, flat, bevelled edged tablets plain on both the surfaces having characteristic odour
Identification:
To comply with the test for Assay by HPLC
The retention time of major peak in the chromatogram of the assay preparation corresponds to that in the chromatogram of the standard preparation, as obtained in assay. Complies Complies Complies
Average weight
150 mg ± 3%
(145.5 - 154.5 mg) 150.5 mg 150.3 mg 151.3 mg
Diameter :
7.0 mm ± 0.3 mm
(6.7 – 7.3 mm) 7.1 mm 7.1 mm 7.1 mm
Thickness:
3.2 mm ± 0.3 mm
(2.9 – 3.5 mm) 3.2 mm 3.2 mm 3.2 mm
Hardness:
Target 35 N (20 – 50 N) 33N 35 N 38 N
Friability: NMT 1.0% 0.22 % 0.22 % 0.66 %
Loss on drying :
NMT 5.0% 1.93 % 1.59 % 2.36 %
Disintegration time:
Not more than 60 seconds using water at 37°C±2°C without disc 26 Sec 27 sec 26 sec
Uniformity of dosage unit:
The quantity of Zolpidem in each tablet should lie between 85.0% and 115.0% of label claim, Acceptance value <15.0 Min: 99.4 %
Max: 105.8 %
Avg: 102.2%
RSD: 1.9%
AV: 5.3 Min: 97.4 %
Max: 101.2 %
Avg: 98.8 %
RSD: 1.3%
AV: 3.1 Min: 96.2 %
Max: 100.4 %
Avg: 98.6%
RSD: 1.3%
AV: 3.0
Dissolution:
(Paddle, 50 RPM, 900 ml 0.01N Hydrochloric acid) Min: 95.0 %
Max: 101.4 %
Avg: 98.3 %
RSD: 2.3 Min: 95.2 %
Max: 100.0%
Avg: 98.4 %
RSD: 1.6 Min: 94.6 %
Max: 99.6%
Avg: 97.7 %
RSD: 1.9
Assay:
5 mg/tablets
(4.75 – 5.25 mg/tablets) 95.0 – 105.0 % 5.04 mg/tab
100.9 % 4.98 mg/tab
99.6 % 5.04 mg/tab
100.8 %
Fineness of dispersion:
A smooth dispersion should produce which passes through a sieve screen with a nominal mesh aperture of 710 µm Complies Complies Complies
Uniformity of weight:
Not more than 2 of the individual masses deviate from the average mass by more than 5% and none deviates by more than 10% Complies Complies Complies
Related substance:
ND

ND

ND

Zolpidem Impurity A - Not more than 0.20 %
Each unknown impurities – Not more than 0.20% BDL BDL BDL
Total impurities – Not more than 0.50% BDL BDL BDL
Microbial Limit Test :
Total aerobic microbial unit : NMT 1000 cfu/g Less than 10 CFU/g Less than 10 CFU/g Less than 10 CFU/g
Total yeast and mold count : NMT 100 cfu/g Less than 10 CFU/g Less than 10 CFU/g Less than 10 CFU/g
Following pathogens should be absent in 1 g:
Escherichia coli Absent in 1 g Absent in 1 g Absent in 1 g
staphylococcus aureus Absent in 1 g Absent in 1 g Absent in 1 g
Pseudomonas aeruginosa Absent in 1 g Absent in 1 g Absent in 1 g
salmonella species should be absent in 10 g. Absent in 10 g Absent in 10 g Absent in 10 g
Actual batch yield of compressed tablets 98.65 % 98.94 % 98.51 %

TABLE 8
Tests 1 2 3
Description White to off white, round, flat, bevelled edged tablets plain on both surface having characteristic odour, packed in Aluminum – Aluminum blister. White to off white, round, flat, bevelled edged tablets plain on both surface having characteristic odour, packed in Aluminum – Aluminum blister. White to off white, round, flat, bevelled edged tablets plain on both surface having characteristic odour, packed in Aluminum – Aluminum blister.
Identification:
To comply with the test for Assay by HPLC
The retention time of major peak in the chromatogram of the assay preparation corresponds to that in the chromatogram of the standard preparation, as obtained in assay. Complies Complies Complies
Average weight
150 mg ± 3%
(145.5 - 154.5 mg) 150.67 mg 152.02 mg 151.46 mg
Diameter :
7.0 mm ± 0.3 mm
(6.7 – 7.3 mm) 7.1 mm 7.1 mm 7.1 mm
Thickness:
3.2 mm ± 0.3 mm
(2.9 – 3.5 mm) 3.2 mm 3.2 mm 3.2 mm
Hardness:
Target 35 N (20 – 50 N) 41N 42 N 41 N
Friability: NMT 1.0% 0.31 % 0.39 % 0.33 %
Fineness of dispersion:
A smooth dispersion should produce which passes through a sieve screen with a nominal mesh aperture of 710 µm. Complies Complies Complies
Loss on drying :
NMT 5.0% 1.83 % 1.55 % 1.90 %
Disintegration time:
Not more than 60 seconds using water at 37°C±2°C without disc 23 Sec 18 sec 23 sec
Uniformity of dosage unit:
The quantity of Zolpidem in each tablet should lie between 85.0% and 115.0% of label claim, Acceptance value <15.0 Min: 99.4 %
Max: 105.8 %
Avg: 102.2%
RSD: 1.9%
AV: 5.3 Min: 97.4 %
Max: 101.2 %
Avg: 98.8 %
RSD: 1.3%
AV: 3.1 Min: 96.2 %
Max: 100.4 %
Avg: 98.6%
RSD: 1.3%
AV: 3.0
Leak Test:
Complies as per current SOP No. PR/OP-29 Complies Complies Complies
Dissolution:
(Paddle, 50 RPM, 900 ml 0.01N Hydrochloric acid) Min: 99.4 %
Max: 101.6 %
Avg: 100.3 %
RSD: 0.9 Min: 98.2 %
Max: 101.4 %
Avg: 99.6 %
RSD: 1.2 Min: 99.8 %
Max: 102.4%
Avg: 100.6 %
RSD: 1.9
Assay:
5 mg/tablets
(4.75 – 5.25 mg/tablets) 95.0 – 105.0 % 4.97 mg/tab
99.3 % 5.01 mg/tab
100.3 % 4.98 mg/tab
99.6 %
Related substance:
ND

ND

ND

Zolpidem Impurity A - Not more than 0.20 %
Each unknown impurities – Not more than 0.20% BDL BDL BDL
Total impurities – Not more than 0.50% BDL BDL BDL
Microbial Limit Test :
Total aerobic microbial unit : NMT 1000 cfu/g Less than 10 CFU/g Less than 10 CFU/g Less than 10 CFU/g
Total yeast and mold count : NMT 100 cfu/g Less than 10 CFU/g Less than 10 CFU/g Less than 10 CFU/g
Following pathogens should be absent in 1 g:
Escherichia coli Absent in 1 g Absent in 1 g Absent in 1 g
staphylococcus aureus Absent in 1 g Absent in 1 g Absent in 1 g
Pseudomonas aeruginosa Absent in 1 g Absent in 1 g Absent in 1 g
salmonella species should be absent in 10 g. Absent in 10 g Absent in 10 g Absent in 10 g
Packing % yield 99.36 % 99.0 % 99.08 %

EXAMPLE 2

[0050] In Example 2, a process for preparing a 10 milligram (mg) zolpidem compositions is described. The process for preparing zolpidem compositions of the present invention was initiated by physically mixing 10 mg of zolpidem tartrate with 80 mg of polacrillin potassium. The mix so formed is sieved/sifted through a 36 mesh fitted with vibratory sifter to form a sifted mass of zolpidem tartrate and polacrillin potassium. Further, the sifted mass of zolpidem tartrate and polacrillin potassium are loaded and blended in the conta blender (rotating blender) to form the taste masked dry mix. The blending is done in 120 litre conta blender for 60 minutes at the blender speed of 8 revolutions per minute (RPM). Thereafter, the taste masked dry mix is unloaded in a double poly bag lined HDPE container and labeled properly from inside and outside of container
[0051] Next, the flavor blend is prepared by mixing 171.5 mg of Pharmaburst B2, 26 mg of lactose monohydrate, 3 mg of colloidal silicon dioxide anhydrous, 5 mg of sweetener and 1.5 mg of flavorant with each other. The mix so formed at is sieved/sifted through a 36 mesh fitted with vibratory sifter to form a sifted flavor blend. Further, the sifted flavor blend is loaded and blended in the conta blender to form flavor blend. In one embodiment, the blending is done in 120 litre conta blender for 20 minutes at the blender speed of 8 RPM. Thereafter, 50% of flavor blend is unloaded in a double poly bag lined HDPE container and labeled properly from inside and outside of container.
[0052] Next, the Intermediate blend is formed by blending of taste masked dry mix and flavor blend. More specifically, the first step comprises adding taste masked dry mix to 50% of the flavor blend in a contra blender bin. In a second step, the remaining 50% of the flavor blend is added. The blending is done in 120 litre conta blender for 30 minutes at the blender speed of 8 RPM.
[0053] Thereafter, ready to compress granules is prepared by adding 3 mg of magnesium stearate (as a lubricant) to the intermediate blend. The sieving/sifting is done through a 40 mesh fitted with vibratory sifter to form a sifted ready to compress granules. Further, the sifted ready to compress granules is blended with intermediate blend as illustrated in the conta blender to form ready to compress granules. The blending is done in 120 litre conta blender for 5 minutes at the blender speed of 8 RPM.
[0054] Finally, 10 mg of zolpidem compositions is formed by compressing the ready to compress granules. The compression is performed using rotary tablet compression machine at a speed of about 25 revolutions per minute. Specifically, the ready to compress granules are compressed from 3.4 using rotatory tablet compression machine fitted with 10.0 mm round flat bevelled punches and dies using the tablet compression parameters described in below table with tablet compression Machine speed of about 25 revolutions per minute. Also, referring to Table 9 below illustrated below are the parameters by which the lubricated pre- compression composition is compressed:-
TABLE 9

Sr. No. PARAMETERS STANDARD LIMITS
1 Appearance White to off white, round, flat bevelled edged tablets plain on both the surface having characteristic odour.
2 Punch description 10 mm round flat beveled edge punches with corresponding dies
3 Weight of 20 tablets 6.0 g 6.0 g ± 3 %
(5.82 g – 6.18 g)
4 Individual tablet weight 300 mg 300 mg ± 5 %
(285 mg – 315 mg)
5 Thickness 3.2 mm 3.2 mm ± 0.3 mm
(2.9 – 3.5 mm)
6 Diameter 10.0 mm 10.00 mm ± 0.3 mm
(9.7 - 10.3 mm)
7 Hardness 35 N 20 N – 50 N
8 Disintegration time NMT 60 second using water at 370C ± 2°C without disc NMT 60 second using water at 370C ± 2°C without disc
9 Friability NMT 1.0 % NMT 1.0 %

[0055] Although particular compression parameters are mentioned above, it will be evident to a person skilled in the art to modify parameters based on obvious variations.
[0056] Further, In Table 10 below, the different ingredients of the zolpidem compositions are depicted along with details on pharmacopeial reference, the vendor from whom the ingredient was obtained, percent by weight of each ingredient and weight in mg of each ingredient. In tables below “(a)” denotes quantity of API shall be considered based on moisture content and % assay potency and “(b)” denotes quantity of API shall be adjusted against quantity of polacrilin potassium (kyron T -134)
TABLE 10
Ingredients Manufacturer Quality Referential % w/w mg/
tab

Taste masked dry mix
Zolpidem Tartrate (a) (Particle size D90 = 50µ ) Aarti drugs Ltd Ph.Eur 3.33 10.0
Polacrilin Potassium (b) (Kyron T -134) Corel Pharma Chem USP 26.66 80.0
Flavor Blend
Pharmaburst B2 SPI Pharma In-house 57.17 171.5
Lactose monohydrate (Supertab 30 GR) DMV, Fonterra Excipients/DFE Pharma Ph.Eur 8.67 26.0
Aspartame Nutrasweets Ph.Eur 1.67 5.0
Colloidal silicon dioxide anhydrous
(Aerosil 200) Evonik Ph.Eur 1.0 3.0
Flavor- Black Current
(502009 AP0551) Firmenich In-house 0.5 1.5
Lubrication
Magnesium stearate Ferro Corporation Ph.Eur 1.0 3.0
Total 100.0 300.0
[0057] Specifically, the process and composition details described in Example 9 and Table 10 is used for preparing 10 mg zolpidem compositions. Multiple experiments were conducted to form 10 mg zolpidem compositions, i.e, to form zolpidem compositions comprising 10 mg of zolpidem Tartrate. For example, experiment for batches 4, 5 and 6 were conducted for forming 10 mg zolpidem compositions. It was found all batches resulted in substantially the same content indicating consistency in uniformity of content that is desirable for lower dosage compositions of 10 mg. Such properties for the different batches are illustrated in Tables below.
[0058] Table 11 below illustrates the batch quantity for 1,25,000 tablets in kilograms (kg). Table 12 below illustrates the analytical result of taste masked dry mix solution for different batches. Table 13 below illustrates the analytical result of unlubricated granules. In Tables 12 and 13, it can be concluded, blend uniformity test of zolpidem Tartrate for all three batches shows that the drug content at all the ten points are within the specification and % RSD value less than 5, there by demonstrating adequate distribution of the drug. Table 14 illustrates the analytical result of lubricated granules. In Table 14, it can be concluded, assay and blend uniformity test for zolpidem tartrate content was within the specification indicating uniform distribution of drug and also uniform distribution of particle size was observed in all three batches.
[0059] Table 15 illustrates the analytical result of bulk tablets. In Table 15, it can be concluded, physical parameters and analytical results (Content of uniformity, Assay, dissolution, RS and Micro) of Zolpidem Tartrate were found within the specification for all three batches. Thus it concludes that direct compression process is suitable and reproducible for manufacturing of Zolpidem Tartrate sublingual orally disintegrating tablets. Table 16 illustrates the analytical result of pack tablets. In Table 16, it can be concluded, tablets were pack in Alu – Alu blister pack. Samples analysis results were complies with physical, chemical and Microbial limit tests specifications.
TABLE 11

Ingredients Batch Quantity for 1,25,000 tablets (kg)
4 5 6
Zolpidem Tartrate (a) (Particle size D90 = 50µ ) 1.274(a) 1.287(a) 1.250(a)
Polacrilin Potassium (b) (Kyron T -134) 9.976 (b) 9.963(b) 10.000 (b)
Flavor Blend
Pharmaburst B2 21.44 21.44 21.44
Lactose monohydrate (Supertab 30 GR) 3.25 3.25 3.25
Aspartame 0.625 0.625 0.625
Colloidal silicon dioxide anhydrous
(Aerosil 200) 0.375 0.375 0.375
Flavor- Black Current
(502009 AP0551) 0.188 0.188 0.188
Lubrication
Magnesium stearate 0.375 0.375 0.375
Total 37.50 37.50 37.50

TABLE 12
Taste masked dry mix Yield 4 5 6
Theoretical yield 11.24 kg 11.24 kg 11.24 kg
Practical yield in kg 11.22 kg 11.24 kg 11.22 kg
% Practical yield 99.82 % 100.0 % 99.82%

TABLE 13
Tests 4 5 6
Appearance White to off white granules having characteristic odour White to off white granules having characteristic odour White to off white granules having characteristic odour
Blend uniformity:
33.67 mg/g
30.30 to 37.04 mg/g
(90 .0 % to 110.0% of L.C)
RSD: Not more than 5.0%
Min: 97.8 %
Max: 103.3 %
Avg: 99.9 %
RSD: 1.7% Min: 97.0 %
Max: 102.2 %
Avg: 99.1%
RSD: 1.6 % Min: 95.0 %
Max: 101.9 %
Avg: 97.9 %
RSD: 2.1%

TABLE 14
Tests 4 5 6
Appearance White to off white granules having characteristic odour White to off white granules having characteristic odour White to off white granules having characteristic odour
Loss on drying:
Not more than 5% 2.35 % 1.36 % 1.67 %
Assay:
33.33 mg/g
31.66 – 35.0 mg/g
(95 – 105% of L.C) 33.71 mg/gm
101.2 % 33.10 mg/gm
99.3 % 33.65 mg/gm
101.0 %
Particle size distribution:
Not less than 95% particles passes through 500µ 20 # = 0.10 %
35#= 0.38 %
40# = 0.88 %
50 # = 2.59 %
60 # = 5.32 %
80# = 25.58 %
100 # = 44.03 %
120 # = 56.41 %
Below 120# = 99.36 % 20 # = 0.12 %
35#= 0.94 %
40# = 1.55 %
50 # = 3.23 %
60 # = 5.92 %
80# = 26.18 %
100 # = 44.68 %
120 # = 57.13 %
Below 120# = 99.97 % 20 # = 0.08 %
35#= 0.78 %
40# = 1.34 %
50 # = 2.99 %
60 # = 5.61 %
80# = 25.85 %
100 # = 44.32 %
120 # = 56.76 %
Below 120# = 99.64 %
Bulk density 0.61 gm/ml 0.60 gm/ml 0.61 gm/ml
Tapped density 0.81 gm/ml 0.82 gm/ml 0.84 gm/ml
Blend uniformity:
33.33 mg/g
30.00 – 36.66 mg/g
(90.0 % – 110.0 % of L.C)
RSD: Not more than 5.0 % Min: 97.0 %
Max: 102.1 %
Avg: 99.9 %
RSD: 1.7% Min: 96.8 %
Max: 101.2 %
Avg: 98.7 %
RSD: 1.6% Min: 96.7 %
Max: 105.2 %
Avg: 99.5 %
RSD: 2.4 %
Related substance:
ND

ND

ND

Zolpidem Impurity A – Not more than 0.20 %
Each unknown impurities –
Not more than 0.20% BDL BDL BDL
Total impurities – Not more than 0.50% BDL BDL BDL
Microbial Limit Test :
Total aerobic microbial unit : NMT 1000 cfu/g Less than 10 CFU/g Less than 10 CFU/g Less than 10 CFU/g
Total yeast and mold count : NMT 100 cfu/g Less than 10 CFU/g Less than 10 CFU/g Less than 10 CFU/g
Following pathogens should be absent in 1 g:
Escherichia coli Absent in 1 g Absent in 1 g Absent in 1 g
staphylococcus aureus Absent in 1 g Absent in 1 g Absent in 1 g
Pseudomonas aeruginosa Absent in 1 g Absent in 1 g Absent in 1 g
salmonella species should be absent in 10 g. Absent in 10 g Absent in 10 g Absent in 10 g
Theoretical weight of granules
Quantity of granules obtained 36.70 kg 36.80 kg 36.84 kg
Yield of granules 99.79 % 99.86 % 99.81 %
Process Loss 0.08 kg 0.05 kg 0.07 kg

TABLE 15
Tests 4 5 6
Description White to off white, round, flat, bevelled edged tablets plain on both the surfaces having characteristic odour White to off white, round, flat, bevelled edged tablets plain on both the surfaces having characteristic odour White to off white, round, flat, bevelled edged tablets plain on both the surfaces having characteristic odour
Identification:
To comply with the test for Assay by HPLC
The retention time of major peak in the chromatogram of the assay preparation corresponds to that in the chromatogram of the standard preparation, as obtained in assay. Complies Complies Complies
Average weight
150 mg ± 3%
(145.5 - 154.5 mg) 301.6 mg 295.6 mg 298.2 mg
Diameter :
7.0 mm ± 0.3 mm
(6.7 – 7.3 mm) 10.1 mm 10.1 mm 10.1 mm
Thickness:
3.2 mm ± 0.3 mm
(2.9 – 3.5 mm) 3.2 mm 3.2 mm 3.2 mm
Hardness:
Target 35 N (20 – 50 N) 41N 42 N 44 N
Friability: NMT 1.0% 0.44 % 0.31 % 0.21 %
Loss on drying :
NMT 5.0% 2.22 % 1.84 % 2.65 %
Disintegration time:
Not more than 60 seconds using water at 37°C±2°C without disc 26 Sec 26 sec 28 sec
Uniformity of dosage unit:
The quantity of Zolpidem in each tablet should lie between 85.0% and 115.0% of label claim, Acceptance value <15.0 Min: 100.1 %
Max: 103.8 %
Avg: 101.5%
RSD: 1.4%
AV: 3.4 Min: 99.2 %
Max: 104.2 %
Avg: 99.2 %
RSD: 1.8 %
AV: 4.5 Min: 100.1 %
Max: 104.1 %
Avg: 101.6%
RSD: 1.4 %
AV: 3.5
Dissolution:
(Paddle, 50 RPM, 900 ml 0.01N Hydrochloric acid) Min: 100.4 %
Max: 102.9 %
Avg: 101.9 %
RSD: 0.8 Min: 97.0 %
Max: 105.6 %
Avg: 101.5 %
RSD: 3.0 Min: 98.1 %
Max: 99.4%
Avg: 98.6%
RSD: 0.4
Assay:
5 mg/tablets
(4.75 – 5.25 mg/tablets) 95.0 – 105.0 % 10.05 mg/tab
100.5 % 9.94 mg/tab
99.4 % 9.99 mg/tab
99.9 %
Fineness of dispersion:
A smooth dispersion should produce which passes through a sieve screen with a nominal mesh aperture of 710 µm Complies Complies Complies
Uniformity of weight:
Not more than 2 of the individual masses deviate from the average mass by more than 5% and none deviates by more than 10% Complies Complies Complies
Related substance:
ND

ND

ND

Zolpidem Impurity A - Not more than 0.20 %
Each unknown impurities – Not more than 0.20% BDL BDL BDL
Total impurities – Not more than 0.50% BDL BDL BDL
Microbial Limit Test :
Total aerobic microbial unit : NMT 1000 cfu/g Less than 10 CFU/g Less than 10 CFU/g Less than 10 CFU/g
Total yeast and mold count : NMT 100 cfu/g Less than 10 CFU/g Less than 10 CFU/g Less than 10 CFU/g
Following pathogens should be absent in 1 g:
Escherichia coli Absent in 1 g Absent in 1 g Absent in 1 g
staphylococcus aureus Absent in 1 g Absent in 1 g Absent in 1 g
Pseudomonas aeruginosa Absent in 1 g Absent in 1 g Absent in 1 g
salmonella species should be absent in 10 g. Absent in 10 g Absent in 10 g Absent in 10 g
Actual batch yield of compressed tablets 98.48 % 98.70 % 98.65 %

TABLE 16
Tests 4 5 6
Description White to off white, round, flat, bevelled edged tablets plain on both surface having characteristic odour, packed in Aluminum – Aluminum blister. White to off white, round, flat, bevelled edged tablets plain on both surface having characteristic odour, packed in Aluminum – Aluminum blister. White to off white, round, flat, bevelled edged tablets plain on both surface having characteristic odour, packed in Aluminum – Aluminum blister.
Identification:
To comply with the test for Assay by HPLC
The retention time of major peak in the chromatogram of the assay preparation corresponds to that in the chromatogram of the standard preparation, as obtained in assay. Complies Complies Complies
Average weight
150 mg ± 3%
(145.5 - 154.5 mg) 301.61 mg 301.13 mg 300.52 mg
Diameter :
7.0 mm ± 0.3 mm
(6.7 – 7.3 mm) 10.1 mm 10.1 mm 10.1 mm
Thickness:
3.2 mm ± 0.3 mm
(2.9 – 3.5 mm) 3.2 mm 3.2 mm 3.2 mm
Hardness:
Target 35 N (20 – 50 N) 41N 40 N 39 N
Friability: NMT 1.0% 0.26 % 0.25 % 0.35 %
Fineness of dispersion:
A smooth dispersion should produce which passes through a sieve screen with a nominal mesh aperture of 710 µm. Complies Complies Complies
Loss on drying :
NMT 5.0% 1.34 % 0.82 % 1.09 %
Disintegration time:
Not more than 60 seconds using water at 37°C±2°C without disc 28 Sec 27 sec 30 sec
Uniformity of dosage unit:
The quantity of Zolpidem in each tablet should lie between 85.0% and 115.0% of label claim, Acceptance value <15.0 Min: 100.1 %
Max: 103.8 %
Avg: 101.5%
RSD: 1.4%
AV: 3.4 Min: 99.2 %
Max: 104.2 %
Avg: 99.2 %
RSD: 1.8 %
AV: 4.5 Min: 100.1 %
Max: 104.1 %
Avg: 101.6%
RSD: 1.4 %
AV: 3.5
Leak Test:
Complies as per current SOP No. PR/OP-29 Complies Complies Complies
Dissolution:
(Paddle, 50 RPM, 900 ml 0.01N Hydrochloric acid) Min: 98.3 %
Max: 100.5 %
Avg: 99.4 %
RSD: 0.8 Min: 98.9 %
Max: 101.0 %
Avg: 99.8 %
RSD: 0.9 Min: 98.5 %
Max: 101.6 %
Avg: 99.9 %
RSD: 1.1
Assay:
5 mg/tablets
(4.75 – 5.25 mg/tablets) 95.0 – 105.0 % 9.96 mg/tab
99.6 % 9.94 mg/tab
99.4 % 9.90 mg/tab
99.0 %
Related substance:
ND

ND

ND

Zolpidem Impurity A - Not more than 0.20 %
Each unknown impurities – Not more than 0.20% BDL BDL BDL
Total impurities – Not more than 0.50% BDL BDL BDL
Microbial Limit Test :
Total aerobic microbial unit : NMT 1000 cfu/g Less than 10 CFU/g Less than 10 CFU/g Less than 10 CFU/g
Total yeast and mold count : NMT 100 cfu/g Less than 10 CFU/g Less than 10 CFU/g Less than 10 CFU/g
Following pathogens should be absent in 1 g:
Escherichia coli Absent in 1 g Absent in 1 g Absent in 1 g
staphylococcus aureus Absent in 1 g Absent in 1 g Absent in 1 g
Pseudomonas aeruginosa Absent in 1 g Absent in 1 g Absent in 1 g
salmonella species should be absent in 10 g. Absent in 10 g Absent in 10 g Absent in 10 g
Packing % yield 99.09 % 99.08% 99.92 %

[0060] Further, multiple experiments were conducted to form 10 mg zolpidem compositions for having best taste masking effect with good mouth feel effect. For example, experiment for different batches were conducted for forming 10 mg zolpidem compositions. It was found that 1:8 ratio of zolpidem tartrate and polacrillin potassium is appropriate for taste masking with mixing time of 60 minutes. Further, it is also found that black current flavor is suitable for taste masking with good mouth feel effect. Such properties for the different batches are illustrated in Tables below. Table 17 illustrates the taste masking effect aspect based on ratio of drug to the ion-exchange resin. Table 18 below illustrates the taste masking effect with flavorant. Table 19 below illustrates the taste masking effect with mixing time.
TABLE 17
Batch No. Drug + Kyron T 134 ratio Result
7 1:8 No bitter taste
8 1:4 Bitter taste
9 1:2 Very bitter taste

TABLE 18
Batch No. Drug + Flavor Result
10 No flavor highly bitter
11 Strawberry flavor slightly bitter
12 Black current flavor with 1% concentration Bitter less with good mouth feel effect.
13 Black current flavor with 0.5% concentration Bitter less with good mouth feel effect.
14 Black current flavor with 0.25% concentration Bitter with no good mouth feel effect.

TABLE 19

Drug + Kyron T 134 ratio
1:8 Time for mixing Result
60 min No bitter taste
30 min Bitter taste
15 min Very bitter taste

[0061] The foregoing descriptions of specific embodiments of the present invention have been presented for purposes of illustration and description. They are not intended to be exhaustive or to limit the present invention to the precise forms disclosed, and obviously many modifications and variations are possible in light of the above teaching. The embodiments were chosen and described in order to best explain the principles of the present invention and its practical application, to thereby enable others skilled in the art to best utilize the present invention and various embodiments with various modifications as are suited to the particular use contemplated. (It is understood that various omission and substitutions of equivalents are contemplated as circumstance may suggest or render expedient, but such are intended to cover the application or implementation without departing from the spirit or scope of the claims of the present invention).