Field of the Invention:
The present invention relates to a new controlled release dosage form for metformin or
its pharmaceutically acceptable salts with no burst effect.
Background of Invention:
Metformin is an antihyperglycemic agent of the biguanide class used in the treatment of
non-insulin dependent diabetes mellitus.
Metformin hydrochloride has intrinsically poor permeability in the lower portion of the
gastrointestinal tract leading to absorption almost exclusively in the upper part of the
gastrointestinal tract. Its oral bioavailability is in the range of 40 to 60% decreasing with
increasing dosage, which suggests some kind of saturable absorption process, or
permeability/transit time limited absorption. It also has very high water solubility. (>300
mg/ml at 25°C) This can lead to difficulty in providing a slow release rate from a
formulation and problems in controlling the initial burst of drug from such a formulation.
These two difficulties are further compounded by the high unit dose, 500 mg per tablet or
more, usually required for metformin hydrochloride, Drugs that have absorption limited to
the upper gastrointestinal tract coupled with poor absorption in the distal small intestine,
large intestine and colon are usually regarded as inappropriate candidates for
formulation into oral controlled delivery systems.
Oral controlled release delivery systems function by releasing their payload of drug over
an extended period of time following administration. Thus, controlled release dosage
forms may only spend a relatively short period in the regions of the gastrointestinal tract
where good absorption of certain drugs can occur. The dosage form will pass on to
regions of the intestine where absorption of certain drugs is poor or non-existent, still
releasing its contained drug albeit with a significant percentage of its payload still to be
delivered. Drug when released from the dosage form in the circumstances described will
not be absorbed. Thus, administration of a drug subject to a window of absorption in a
conventional controlled release delivery system can lead to subtherapeutic blood levels
and ineffective treatment of the disease state for which the drug was intended.
Drugs with very high solubility in water (for example, greater than 100 mg/ml) can be
difficult to formulate into a controlled release oral dosage form. Solubility is a driving
2

force for a drug substance to dissolve in water; the greater the solubility the greater the
rate of dissolution when all other factors are maintained constant.
In a controlled release dosage form, the formulator tries to reduce the rate of dissolution
by, for example, embedding the drug in a polymeric matrix or surrounding it with a
polymeric barrier membrane through which drug must diffuse to be released for
absorption. To reduce the rate of release of drug from the dosage form to an appropriate
level consistent with the blood level profile desired for a drug possessing very high water
solubility, very large amounts of polymer would be required for the matrix or barrier
membrane. If the total daily dose of drug to be delivered is of the order of only a few
milligrams this may be feasible, but many drugs having the solubility properties
described require total daily doses of the order of many hundreds of milligrams. Whilst it
is possible to create oral controlled release dosage forms for such products by use of
large amounts of polymer, an unacceptably large dosage form may result.
A further problem with highly water soluble drugs formulated into a controlled release
dosage form is that a significant and variable "burst" of drug can occur from these
systems. The burst of highly water-soluble drug is the initial rapid release of drug that
occurs from oral controlled release dosage forms when first contacting fluid, such as
gastric fluids, prior to release controlling mechanisms of the dosage form establishing
themselves and a stable release rate being provided. Hydration of any polymer matrix
used to formulate the dosage form is a pre-requirement of establishing a stable release
rate. However, if the polymer used is slow to hydrate, then an undesirable variable burst
can occur.
In the prior art, many techniques have been used to provide controlled and extended-
release pharmaceutical dosage forms in order to maintain therapeutic levels of
medicaments and to minimize the effects of missed doses of drugs caused by a lack of
patient compliance. There are number of different modified release dosage forms
available commercially. However, some of these are expensive to manufacture and can
be difficult to swallow, particularly in elderly patients.
Some of the techniques to make modified release dosage form of drugs as described in
prior art are as follows:
3

W099/47128 discloses a method of prolonging the release of a highly water- soluble
drug. A biphasic controlled release delivery system for metformin hydrochloride, which
has prolonged gastric residence and that swells following hydration are described.
U.S. Pat. No. 6,099,859 describes a controlled release antihyperglycemic tablet, which
has a semipermeable coating on a core with a passageway formed in the membrane to
allow for osmotic diffusion of the drug from the core.
WO 02/28181 describes a monolithic sustained release formulation of metformin
hydrochloride. The method of making the formulation involves hot melt granulation
followed by wet granulation with binders of extrusion.
WO 2004/012699 A2 discloses modified release dosage form comprising of a highly
soluble active ingredient, which utilizes dual retard technique comprising micro matrix
particles containing active ingredient (s) one or more hydrophobic release controlling
agents and coating of one or more hydrophobic release controlling agents.
US 6475521 describe biphasic controlled release delivery system for high solubility
pharmaceutical using biphasic controlled release delivery system for treating diabetes.
US application US2004/0086566 describes a waxy matrix dosage forms comprising a
pharmaceutically effective amount of metformin and a waxy matrix material
Thus the present invention provides a novel controlled release formulation of metformin
or its pharmaceutically acceptable salts thereof, which provide freedom from burst effect,
associated with formulation of controlled release of highly water-soluble.
Objects of the invention
The object of the present invention to provide a controlled release oral pharmaceutical
dosage form providing no burst effect comprising as an active ingredient metformin
hydrochloride and controlled release excipient.
4

Another object of the present invention is to provide a controlled release oral
pharmaceutical dosage form providing no burst effect comprising (1) a core comprising
as an active ingredient metformin or its pharmaceutical acceptable salts, hydrophilic
substance and / or hydrophobic substance (2) coating, which is permeable to drug as
well as to gastrointestinal fluids.
Another object of the present invention is to provide a method of preparing controlled
release oral pharmaceutical dosage form providing no burst effect comprising.
Another object of the present invention is to provide the dissolution profile of an oral
controlled release oral pharmaceutical dosage form of metformin hydrochloride
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed towards a controlled release oral pharmaceutical
dosage form comprising as an active ingredient metformin or its pharmaceutically
acceptable salts and controlled release excipient. The formulation of the present
invention provides controlled release of metformin hydrochloride with no burst release
which is commonly associted with highly water soluble drug.
The present invention is directed towards a controlled release oral pharmaceutical
dosage form comprising (as an active ingredient metformin or its pharmaceutically
acceptable salts, and controlled release excipient. The formulation of the present
invention provides controlled release of metformin hydrochloride with no burst release
which is commonly associted with highly water soluble drug.
Another aspect of the present invention is to provide a controlled release oral
pharmaceutical dosage form comprising (1) a core comprising as an active ingredient
metformin or its pharmaceutically acceptable salts, hydrophilic substance and / or
hydrophobic subsatnce (2) permeable coating
Active ingredient means metformin or pharmaceutically acceptable salts or derivatives
or prodrug or metabolites there of.
5

"Controlled release," means drug delivery system releasing the drug at a predetermined
rate, locally or systemically, for a specified period of time. Controlled release can be
used interchangeably with prolonged release, programmed release, timed release,
extended release, sustained release, modified release, slow release and other such
dosage forms.
By "pharmaceutically acceptable" is meant a carrier comprised of a material that is not
biologically or otherwise undesirable.
Pharmaceutically acceptable excipients include but are not limited to binders, diluents,
lubricants, glidants and surface-active agents.
The dosage form according to present invention may be tablet, capsules, pellet, bead,
spheroids, microcapsules, mini tablet, powder, granules and others.
In one of the embodiments of the present invention there is a controlled release
metformin hydrochloride formulation that comprises of core comprising metformin
hydrochloride, a hydrophilic substance and/ or hydrophobic substance and coating with
an copolymers of acrylic acid and methacrylic acid esters.
It has been observed that although it is possible to produce controlled release
formulation comprising metformin hydrochloride, hydrophilic substance and/ or
hydrophobic substance, such a formulation provides a burst release since metformin
hydrochloride is highly soluble active ingredient.
It has been found that when such a core formulation is further coated with copolymers of
acrylic acid and methacrylic acid esters which are commercially known as Eudragits® or
mixture of copolymers of acrylic acid and methacrylic acid esters, the burst release of
the active ingredient is avoided.
The pharmaceutical composition of the present invention contain, for example, form
about 0.1% to 90% of metformin.
6

Hydrophilic substance which may be used in the present invention includes
hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, vinyl acetate
copolymers, polysaccharides as alginates, xanthan gum, Chitosan, carrageenan,
dextran and the like, polyalkylene oxides as polyethylene oxide and the likes,
methaacrylic acid copolymers, maleic anhydride/methyl vinyl ether copolymers,
carbomer (Carbopol(TM)), guar gum, locust bean gum, poly vinyl acetate, polyvinyl
alcohol and the like.
Hydrophobic substance includes acrylates, cellulose derivatives as ethylcellulose,
cellulose acetate and the likes, methaacrylates, high molecular weight polyvinyl alcohols,
waxes, hydrogenated vegetable oil, purified grades of beeswax; fatty acids; long chain
fatty alcohols, such as cetyl alcohol, myristyl alcohol, and stearyl alcohol; glycerides
such as glyceryl esters of fatty acids like glyceryl monostearate, glyceryl distearate,
glyceryl esters of hydrogenated castor oil and the like; oils such as mineral oil and the
like, or acetylated glycerides; stearic acid , paraffin, camauba wax, talc; and the stearate
salts such as calcium, magnesium, zinc and other materials known to one of ordinary
skill in the art.
The formulation of the present invention may further include other excipients such as
binders, diluents, lubricants, disintegrating agents, glidants, stabilzers, and surface-
active agents.
The amount of excinients smn!o"ed will denend unon how much active anent is to be
used. One excipient can perform more than one function.
Binders include, but are not limited to, starches such as potato starch, wheat starch,
corn starch; microcrystalline cellulose, celluloses such as hydroxypropyl cellulose,
hydroxyethyl cellulose, hydroxypropylmethyl cellulose (HPMC), ethyl cellulose, sodium
carboxy methyl cellulose; natural gums like acacia, alginic acid, guar gum; liquid
glucose, dextrin, povidone, syrup, polyethylene oxide, polyvinyl pyrrolidone, poly-N-vinyl
amide, polyethylene glycol, gelatin, poly propylene glycol, tragacanth, combinations
there of and other materials known to one of ordinary skill in the art and mixtures thereof.
Fillers or diluents, which include, but are not limited to confectioner's sugar,
compressible sugar, dextrates, dextrin, dextrose, fructose, lactitol, mannitol, sucrose,
7

starch, lactose, xylitol, sorbitol, talc, microcrystalline cellulose, calcium carbonate,
calcium phosphate dibasic or tribasic, calcium sulphate, and the like can be used.
Disintegrating agents, which may be used, includes crospovidone, croscarmellose,
sodium starch glycolate and the likes.
Lubricants may be selected from, but are not limited to, those conventionally known in
the art such as Mg, Al or Ca or Zn stearate, polyethylene glycol, glyceryl behenate,
mineral oil, sodium stearyl fumarate, stearic acid, hydrogenated vegetable oil and talc.
Glidants include, but are not limited to, silicon dioxide; magnesium trisilicate, powdered
cellulose, starch, talc and tribasic calcium phosphate, calcium silicate, magnesium
silicate, colloidal silicon dioxide, silicon hydrogel and other materials known to one of
ordinary skill in the art.
The present formulations may optionally contain a surface-active agent. The preferred
agent is poloaxmer. However, other agents may also be employed such as dioctyl
sodium sulfosuccinate (DSS), triethanolamine, sodium lauryl sulphate (SLS),
polyoxyethylene sorbitan and poloxalkol derivatives, quaternary ammonium salts or
other pharmaceutically acceptable surface-active agents known to one ordinary skilled in
the art.
The present invention further comprise of coating. The coating over the core is a
permeable coating. The coating is permeable in that water can penetrate the coating and
the active agent can be released there through. The polymers may be cross-linked
polyvinyl alcohol, poly (lactic acid) (PLA), poly (lactic-co-glycolic acid) (PLGA), poly
(caprolactone) (PCL), polyolefins, polyvinyl chlorides, cross- linked gelatins, insoluble
and non-erodable cellulose, acylated cellulose, esterified celluloses, cellulose acetate
propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose acetate
diethylaminoacetate, polyurethanes, polycarbonates, acrylic polymer, cellulose ethers,
and microporous polymers formed by co-precipitation of a polycation and a polyanion
modified insoluble collagen. The coating is preferably comprised of an acrylic polymer.
Within the invention, an"acrylic polymer" means a pharmaceutically acceptable
copolymer of methacrylic acid or a salt thereof and an acrylic or methacrylic acid, acid
ester, and/or salt thereof. The amount of coating is usually within 1% to 10%. The
8

appropriate amount will depend on the core, the active agent, and the kind of materials
in the coating and the desired modification of the release.
The coating need not be in physical, direct contact with the core as intervening layers
may instead be present, so long as the coating surrounds or envelops the core.
Preferably the water insoluble coating is disposed on the core.
Thus the present invention comprise of coating comprising copolymers of acrylic acid
and methacrylic acid esters. The coating helps to avoid the burst effect associated with
high solubility active ingredient as metformin hydrochloride. The commercially available
copolymers of acrylic acid and methacrylic acid esters are called as Eudragit®. Eudragit
is available in various grades.
Examples of acrylic polymers include acrylate-methacrylate copolymers, ammonioalkyl
methacrylate copolymers and metacrylic ester copolymers.
In particular, Eudragit RL, RS and NE series are preferred. The coating can contain one
or more acrylic polymers and/or other ingredients including other polymers, surfactants,
plasticizers, pore forming agent etc. Normally, the coating consists primarily of one or
more acrylic polymers. Preferably the acrylic polymer is one or more selected from the
Eudragit RL series (high permeable), Eudragit RS series (low permeable), mixtures
thereof, or Eudragit NE series
All EUDRAGIT® polymers for sustained-release formulations release the drug by
diffusion.
The most preferred copolymers of acrylic acid and methacrylic acid esters are
EUDRAGIT® RL 100 or RL PO or RL30D or RL12.5 and EUDRAGIT® RS 100 or RS
PO or RS 30D or RS 12.5. They are copolymers of acrylic and methacrylic acid esters
with a low content in quaternary ammonium groups. The ammonium groups are present
as salts and make the polymers permeable. EUDRAGIT® RL 100 and EUDRAGIT® RS
100 are colorless, clear to cloudy granules with a faint amine-like odor. EUDRAGIT® RL
PO and EUDRAGIT® RS PO are white powders with a faint amine-like odour.
9

EUDRAGIT® RL 100 / RL PO has 8.85 - 11.96 % ammonio methacrylate units on dry
substance (DS) having an alkali value of 23.9 - 32.3 mg KOH per g dry substance and
EUDRAGIT® RS 100 / EUDRAGIT® RS PO has 4.48 - 6.77 % ammonio methacrylate
units on dry substance and an alkali value: 12.1 -18.3 mg KOH per g DS
EUDRAGIT® RL and EUDRAGIT® RS are water-insoluble, swellable film formers based
on neutral methacrylic acid esters with a small proportion of trimethylammonioethyl
methacrylate chloride. With EUDRAGIT® RL, the molar ratio of the quaternary
ammonium groups to the neutral ester groups is 1:20 (corresponding to about 50 meq./
100 g), with EUDRAGIT® RS this ratio is 1:40 (corresponding to roughly 25 meq./100 g).
Since quaternary ammonium groups determine the swellability and the permeability of
the films in aqueous media, EUDRAGIT® RL, which contains more of these groups,
forms more permeable films with little delaying action. By contrast, and owing to the
reduced content in quaternary ammonium groups, films of EUDRAGIT® RS swell less
easily and are only slightly permeable to active ingredients. Given coherent film coatings
and an adequate layer thickness, it is therefore possible to slow down drug diffusion very
noticeably. EUDRAGIT® RS and RL polymers can be mixed in any ratio to produce films
with different permeability.
For the present invention the coating solution is prepared by mixing Eudragit® RLPO
100 and RSPO100 in different ratio to prepare permeable file coating which controls the
release of metformin hydrochloride and also avoid burst effect. Further the coatinn
solution may also contain other polymers, surfactants, plasticizers etc.
The pharmaceutical composition of the invention can be formed by various methods
known in the art such as by dry granulation, wet granulation, melt granulation, direct
compression, double compression, extrusion spheronization, layering and the like.
Compaction of the blend into coprimate may be carried out using a slugging technique or
roller compaction. The milling of the granules may be carried out according to
conventional milling methods.
10

The process of wet granulation includes aqueous or non-aqueous granulation. The wet
granulation process comprises the admixing of the active ingredient with diluent(s)
and/or rate controlling polymer, and granulation of the blend with the binder mass to
form the wet mass followed by drying and sizing. The binder may optionally be admixed
with the dry blend and granulation performed with aqueous or non-aqueous solvent. The
solvent for the non-aqueous granulation is selected from ethanol, isopropyl alcohol and
dichloromethane.
The following examples are illustrative of the present invention, and the example should
not be considered as limiting the scope of this invention in any way, as these examples
and other equivalents thereof will become apparent to those versed in the art, in the light
of the present disclosure, and the accompanying claims.
A person skilled in the art may make variations and modifications without deviating from
the spirit and scope of the invention. All such modifications and variations are intended
to be included within the scope of the invention.
Examples:
Example 1:

Sr. No. Ingredients %
1. Metformin Hydrochloride 66
2. HPMC K 100 M 17
3. PVP K30 3.5
4 Crosspovidone o r-
O.U
5. MCC PH 102 3.5
6. Aerosil 200 0.8
7 Magnesium Stearate 0.7
8 Coating 2% to 5%weight gain
Procedure:
1) Metformin hydrochloride is granulated with aqueous solution of PVP K30.
2) Mixed granules with HPMC K100M and lubricated with microcrystalline
cellulose, aerosil, crosspovidone and magnesium stearate and compressed.
3) The compressed granules were coated with mixture of Eudragit® RSPO 100
and Eudragit® RLPO 100
11

The dissolution study of coated and uncoated tablet was craried out in 1000ml of
phosphate buffer pH 6.8 in USP Type I apparatus at an RPM of 100.
Dissolution Data:

Time (hrs.) Uncoated % released Coated % released
0 0 0
1 62 6.3
2 79.4 26.2
4 99.2 49.8
6 74.5
8 90
10 97.9
12 101.2
Example 2:

Sr.No. INGREDIENTS %
1 Metformin HCI 60
2 SLS 1
3 HPMCK100M 24
4 HVO (Sterotex) 8
5 MCCPH102 2.5
6 PEG 6000 1.2
7 Aerosil 200 0.6
8 Magnesium Stearate 0.5
Coating 2% to 5% weight gain
The dissolution study of coated and uncoated tablet was craried out in 1000ml of
phosphate buffer pH 6.8 in USP Type I apparatus at an RPM of 100.
Dissolution Data:

Time (hrs.) Uncoated tablet
% release Coated tablet
% release
0 0 0
1 33.5 14.7
4 63.8 53.7
7 80.7 76.6
12 93.8 87.8
Example 3:

Sr.No. Ingredients %
1 Metformin Hydrochloride 71
2 PVPK-30 4
3 HPMCK100LVCR 21
12

4 MCCPH 102 3
5 Aerosil 200 0.5
6 Mg-stearate 0.5
Coating 2% to 5% weight gain
The dissolution study of coated and uncoated tablet was craried out in 1000ml of
phosphate buffer pH 6.8 in USP Type I apparatus at an RPM of 100.
Dissolution Data:

Time (hrs.) Uncoated
% Released Coated
% Released
0 0 0
1 36.8 5.6
2 52.9 18.1
4 75.7 45.6
6 86.5 67.9
8 97.9 84.5
10 99.4 96.3
12 - 103.5
Example 4:

Sr.No. Ingredients %
1 Metformin Hydrochloride 71
2 PVPK-30 4
3 HPMCE15LV 21
4 MCCPH 102 3
5 Aerosil 200 0.5
6 Mg-stearate 0.5
Coating 2% to 5% weight gain
The dissolution study of coated and uncoated tablet was craried out in 1000ml of
phosphate buffer pH 6.8 in USP Type I apparatus at an RPM of 100.
Dissolution profile

Time (hrs.) Uncoated Coated 4% wt. Gain
0 0 0
1 55.8 3.4
2 72.8 13.6
4 94.4 45.8
6 96.9 69.5
8 98.9 86.2
10 100.9 96.6
12 102.7
13

Coating with permeable polymer such as copolymers of acrylic acid and methacrylic acid
esters avoid the burst effect associated with uncoated tablet comprising as an active
ingredient metformin hydrochloride and controlled release polymer.
The invention having been described, it will be readily apparent to those skilled in the art
that further changes and modifications in actual implementation of the concepts and
embodiments described herein can easily be made or may be learned by practice of the
invention, without departing from the spirit and scope of the invention as defined by the
following claims.
14

We claim:
1) A controlled release oral pharmaceutical dosage form providing no burst effect
comprising as an active ingredient metformin hydrochloride and controlled
release excipient.
2) A controlled release oral pharmaceutical dosage form according to claim 1, which
is further coated with permeable coating.
3) A controlled release oral pharmaceutical dosage form according to claim 2,
wherein coating comprise of copolymers of acrylic acid and methacrylic acid
esters.
4) A controlled release oral pharmaceutical dosage form according to claim 1,
wherein the controlled release polymer is a hydrophilic substance or hydrophobic
substance.
5) A controlled release oral pharmaceutical dosage form according to claim 4
wherein hydrophilic substance may be cellulose derivatives, dextrins, starch,
carbohydrate based polymers, natural or hydrophilic gums, alginates, gelatin,
and the likes
6) A controlled release oral pharmaceutical dosage form according to claim 5
wherein, the hydrophilic substance is hydroxypropylmethyl cellulose.
7) A controlled release oral pharmaceutical dosage form according to claim 1
wherein hydrophobic substance may be ethyl cellulose, hydrogenated vegetable
oil, hydroxyethyl cellulose, ammmonio methacrylate copolymers, waxes, fatty
alcohols, fatty acid esters and the like.
8) A controlled release oral pharmaceutical dosage form according to claim 7
wherein the hydrophobic substance is hydrogenated vegetable oil.
9) A controlled release oral pharmaceutical dosage form according to claim 3
wherein copolymers of acrylic acid and methacrylic acid esters may comprise
mixture of copolymers of acrylic acid and methacrylic acid esters type A and
Type B with low content in quaternary ammonium groups.
15

10) A controlled release oral pharmaceutical dosage form providing no burst effect
comprising (1) a core comprising as an active ingredient metformin or its
pharmaceutical acceptable salts, hydrophilic substance and / or hydrophobic
substance (2) coating which is permeable to drug as well as gastrointestinal
fluids.
11) A controlled release oral pharmaceutical dosage form according to claim 10
wherein hydrophilic substance may be cellulose derivatives, dextrins, starch,
carbohydrate based polymers, natural or hydrophilic gums, alginates, gelatin,
and the likes.
12) A controlled release oral pharmaceutical dosage form according to claim 11
wherein, the hydrophilic substance is hydroxypropylmethyl cellulose.
13) A controlled release oral pharmaceutical dosage form according to claim 10
wherein hydrophobic substance may be ethyl cellulose, hydrogenated vegetable
oil, hydroxyethylcellulose, ammmonio methacrylate copolymers, waxes, fatty
alcohols, fatty acid esters and the like.
14) A controlled release oral pharmaceutical dosage form according to claim 13
wherein the hydrophobic polymer is hydrogenated vegetable oil.
15) A controlled release oral pharmaceutical dosage form according to claim 10
wherein permeable coating comprises of copolymers of acrylic acid and
methacrylic acid esters.
16) A method of preparing controlled release oral pharmaceutical dosage form
providing no burst effect comprising (1) preparing granules comprising
metformin hydrochloride and controlled release excipient (2) Lubricating granules
with microcrystalline cellulose, aerosil and magnesium stearate and then
compressing. (3) Compressed core were then coated with copolymers of acrylic
acid and methacrylic acid esters type A and Type B.
16

17) A oral controlled release oral pharmaceutical dosage form of metformin
hydrochloride comprising: a core comprising metformin hydrochloride and
hydroxypropylmethylcellulose and coating comprising copolymers of acrylic acid
and methacrylic acid
(a) Wherein said tablet exhibits the following dissolution profile, when
measured in type I dissolution apparatus, at 100rpm, in 1000ml of 6.8 pH
phosphate buffer
(i) Not more than about 10% of is released after 1 hour
(ii) From about 10% to about 50% of metformin hydrochloride is released
after 4 hours
(iii) Not less than 75% is released after 8 hours.
Dated this 5th day of February 2008

17

The present invention is directed towards a controlled release oral pharmaceutical
dosage form comprising as an active ingredient metformin or its pharmaceutically
acceptable salts and controlled release excipient. The formulation of the present
invention provides controlled release of metformin hydrochloride with no burst release
which is commonly associted with highly water soluble drug.