Claims:We Claim:
1) An improved process for the preparation of Guaifenesin (I),

I
With a specific particle size and its distribution, wherein the process involves the use of heat liberation while crystallization.

2) An improved process for the preparation of Guaifenesin (I), with a specific particle size and its distribution
I
Comprising the steps of:
a. Subjecting pure Guaifenesin oil to dissolve in a solvent or a combination of solvents at an elevated temperature
b. Cooling the resulted mixture from step a by 10-20°C, while stirring at 30-35 RPM at 0.3-0.5°C/minute
c. Increasing the temperature further by 2-7°C
d. further lowering the temperature by 15-45°C
e. filtration and its collection.

3) An improved process for the preparation of Guaifenesin according to step a of claim 2, wherein solvent maybe selected from the group comprising of ester solvents such as ethyl acetate, isopropyl acetate, butyl acetate; halogenated solvents such as methylene chloride, ethylene dichloride, chloroform, chlorobenzene; nitrile solvents such as acetonitrile; alcoholic solvents such as methanol, ethanol, isopropanol, n-butanol; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone; ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran and/or hydrocarbon solvents such as methyl cyclohexane, toluene, cyclohexane, n-hexane, n-heptane 1,4-dioxan, dimethylsulfoxide (DMSO), N,N-dimethyl formamide (DMF), or water.

4) An improved process for the preparation of Guaifenesin according to step a) of claim 2 wherein the temperature range is of 55 to 75°C.

5) An improved process for the preparation of Guaifenesin (I), wherein the particle size distribution is not more than 380µ for D90; is not more than 130µ for D50 and is not more than 80µ for D10.

6) An improved process for the preparation of Guaifenesin (I), according to claim 5, the particle size distribution ranging from 220-380µ for D90; 70-130µ for D50; 25-80µ for D10.

7) An improved process for the preparation of Guaifenesin (I), wherein the particle size distribution preferably ranging from range 250-350µ for D90; 80-115µ for D50 and 35-50µ for D10.

8) An improved process for the preparation of Guaifenesin (I), wherein the range of the ß-isomer impurity is not more than 0.4%.

9) An improved process for the preparation of Guaifenesin (I), wherein the range of the ß-isomer impurity is not more than 0.26%.

10) A process for the preparation of Guaifenesin (I) according to claim 2, wherein Guaifenesin (I) yield obtained = 60% with a Particle size ranging from 220-380µ for D90; 70-130µ for D50; 25-80µ for D10.
, Description:FIELD OF THE INVENTION
The present invention relates to an improved, industrially applicable and commercial scalable crystallization process to yield a highly pure product of Guaifenesin (Formula I) with controlled particle size and its distribution.

I

BACKGROUND OF THE INVENTION
Guaifenesin goes by the IUPAC name 3-(2-methoxyphenoxy)propane-1,2-diol and is structurally represented by the Compound of Formula I.

I

Guaifenesin is an expectorant used in the treatment of cough, as it promotes, as well as facilitates the removal of secretions from the respiratory tract in a warm-blooded animal, principally a human being. It helps to loosen phlegm (mucus) and thins the bronchial secretions to rid the bronchial passageways of bothersome mucus, this enhances the draining of the bronchial tubes and thus relieves the passage of blockage, suffocation, inflammation and eases cough reflex. The US FDA has approved Guaifenesin as 600mg and 1200mg oral extended release tablets under the brand name MUCINEX® by Reckitt Benckiser. The drug is also available as over-the-counter medicine for cough and cold in the form of tablets, extended release tablet, syrups and solution.

From a pharmaceutical stand point Guaifenesin has a typical plasma half-life of approximately one hour and is classified under BCS class I drug as it is known to be a highly water-soluble, is readily absorbed from the intestinal tract, rapidly metabolized and excreted in urine. These parameters are based on the chemical and physical nature of the drug; it is also known that a few physical properties such as salt formation, crystalline form, particle size distribution, flow properties, bulk density etc. have proven to play a pivotal role in the solubility, product yield, purity, stability, dosage, formulation and subsequent bioavailability of the drug.

Crystallization of an ac¬tive pharmaceutical ingredient (API) in par¬ticular is critical for product qualities such as chemical purity and suitable polymor¬phic form, which need to be strictly controlled in order to meet ICH and regulatory guidelines. The API crystallization process and crystal properties have a significant effect during the downstream processing; for example, excess fine or wide particle size distribu¬tion may cause slow filtration and inefficient drying, which may be a major bottleneck of the entire manufacturing process on commercial scale. Application of negative or positive vacuum appears to be an option however this does not yield uniform crystalline nature or the desired particle size owning to the nature of aggregation and clumping.

There appears to be various discloses in the public domain that cover the particle size distribution and its effect in the formulation, however in relation to Guaifenesin, the prior art describes its combinations with other pharmaceutical excipients.

U.S. Publication No. 20130149383 discloses a composition comprising plurality of particles, each particle comprising Guaifenesin, a hydrophobic wax matrix, a stabilizer and a release modifier; wherein the plurality of particles have a mean particle size diameter of from about 20 µm to about 500 µm. The present invention provides an effective particle size of Guaifenesin prepared via a process that involves the use of heat liberation while crystallization, wherein the crystallization process yield a highly pure product with controlled particle size distribution and uniform crystalline nature, this directly has proven to show an increase in the flow properties and enhanced uniformity during composition and also the decrease in the use of excipients.

PCT application WO 2018165781 discloses a composition comprising of microcapsules containing the guaiacol glycerol ether, have a size average particle size is generally between 100 to 1000 microns, with an average particle size between 150 to 800 micron. The present invention provides an effective particle size of Guaifenesin prepared via a process that involves the use of heat liberation while crystallization, wherein the process yield a highly pure product with controlled particle size distribution and uniform crystalline nature, this directly has proven to show an enhanced uniformity during composition and also the improved pharmacokinetics and pharmacodynamics activity.

U.S. Patent No. 7838032 describes a process to manufacture a composition comprising of Guaifenesin and hydroxypropyl methylcelluose Direct Compression -DC (95%) as intermediate granulation using a granulator, providing Guaifenesin DC with a particle size in the range of from about 2 mm to about 150 µm. The present invention provides an effective particle size of Guaifenesin prepared via a process that involves the use of heat liberation while crystallization, wherein the final product has enhanced uniformity this has shown to have an improved physical properties during composition to yield a more efficient formulation.

US Patent application No. 20030012820 disclose method for making a Guaifenesin dosage form by compressing a Guaifenesin composition comprising Guaifenesin and a binder, being in the form of particles with specific particle sizes. The present invention provides an effective particle size of Guaifenesin prepared via a process that involves the use of heat liberation while crystallization, wherein the final product has enhanced uniformity this has shown to have an improved compressing during formulation.

U.S. Patent No. 9814678 describes a manufacturing process for that may be used for various drugs including Guaifenesin; the composition comprising a hydrophilic active ingredient, a hydrophobic matrix material, a stabilizer, and a release modifier wherein the mixture is heated to melt the hydrophobic matrix thereby forming a particle mixture with the particle of diameters ranging from about 50 µm to about 300 µm. The present invention provides an effective particle size of Guaifenesin prepared via a process that involves the use of heat liberation while crystallization, wherein the crystallization process yield a highly pure product with controlled particle size distribution and uniform crystalline nature, this directly has proven to show an increase in the flow properties and enhanced uniformity during composition and also the decrease in the use of excipients.

U.S. Patent No. 6689817 describes a process to manufacture a composition via freeze-drying reaction mixture comprising of Guaifenesin tannate that is further milled into a fine powder typically having a particle size of about 50 to about 200 mesh. The present invention provides an effective particle size of Guaifenesin prepared via a process that involves the use of heat liberation while crystallization, wherein the yield is a highly pure product with controlled particle size distribution and uniform crystalline nature, this directly has proven to show an increase in the flow properties and enhanced uniformity during composition and formulation.

Sherrington et. at. describes the particle size distribution of Guaifenesin based on the sieving analysis and a Fritsch Laborgeratebau vibrator system; of which 75% of the commercial sample was shown to have particle size range of 25 to 71µm.

The inventors of the present invention also found surprisingly increased yields, improved impurity profile wherein the impurity of B (ß-isomer) significantly reduced and the generation of solid waste that was a byproduct of the mother liquor was also minimized to greater extents, this has also lead to an improved assay profile. The process has exhibited desired yield with consistent Particle size and crystalline nature, it was found to be simple, stable, cost effective, economical and commercially scalable.

OBJECT OF INVENTION
The object of the present invention relates to an improved process for the production of Guaifenesin (Formula I) at an industrial level, wherein the crystallization process yield a highly pure product with controlled particle size distribution and uniform crystalline nature.

Another object of the present invention is the applicability of the above as a continues process at a commercial scale to curb wastage, reduce impurity formation, decrease the multiple stages of purification due to the formation of undesired impurities and the use of excess solvents. This process has also proven to be economical and safe to the environment.

Another object of the present invention is the use of the said product from above in pharmaceutical formulation such as tablets, syrups and capsules.

SUMMARY OF INVENTION
The present invention relates to the improved process to yield Guaifenesin (Formula I) with a controlled particle size and its distribution and an improved purity profile.

An embodiment of the present invention provides the process for the crystallization of Guaifenesin and the crystal growth is achieved by slowly reducing the temperature over the period of time at defined rate (dt/T).

An embodiment of the present invention provides of achieving the desired particle size distribution of Guaifenesin is described in the figures mentioned in specification.

In the first embodiment of the present invention, the process of crystalline production involve the use of heat liberation while crystallization.

In an added embodiment of the present invention, the crystallization process comprises of the pure oil of Guaifenesin to be taken in the crystallizer along with an organic solvent or a combination of organic solvents; the temperature is raised to dissolve Guaifenesin (1) then cooled with stirring, it is further observed for the heat liberation while crystallization and the temperature is further gradually decreased by circulating cool to chilled water to yield a highly pure product with reduced particle size distribution and uniform crystalline nature.

In an additional embodiment of the present invention, the temperature to dissolve Guaifenesin is of the range of 50 to 80°C.

In a further embodiment of the present invention, the temperature to dissolve Guaifenesin is preferably of the range of 65 to 70°C.

In an added embodiment of the present invention, the crystallizer stirs at an RPM ranging from 30 to 45.

In an added embodiment of the present invention, the temperature decreases gradually by 0.2-1.5°C/minute.

In an additional embodiment of the present invention, the organic solvent maybe selected form the group comprising of ester solvents such as ethyl acetate, isopropyl acetate, butyl acetate; halogenated solvents such as methylene chloride, ethylene dichloride, chloroform, chlorobenzene; nitrile solvents such as acetonitrile; alcoholic solvents such as methanol, ethanol, isopropanol, n-butanol; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone; ether solvents such as diethyl ether, diisopropylether, tetrahydrofuran and/or hydrocarbon solvents such as methyl cyclohexane, toluene, cyclohexane, n-hexane, n-heptane.

In a further embodiment of the present invention, the crystallization process yields a product with high purity and controlled ß-isomer impurity.

In another embodiment of the present invention, the crystallization process yields a product with the particle size distribution is not more than 380µ for D90; is not more than 130µ for D50 and is not more than 80µ for D10.

In another embodiment of the present invention, the crystallization process yields a product with the particle size distribution ranging from 220-380µ for D90; 70-130µ for D50; 25-80µ for D10.

In an added embodiment of the present invention, the crystallization process yields a product with the particle size distribution preferably ranging from range 250-350µ for D90; 80-115µ for D50 and 35-50µ for D10.

In a further embodiment of the present invention, the crystallization process yields a product improved impurity profile wherein the impurity of B (ß-isomer) significantly controlled, also the generation of solid waste that was a byproduct of the mother liquor was also minimized to greater extents, this has also lead to an improved assay profile.

In an alternative embodiment of the present invention, the crystallization process curbs wastage, reduce impurity formation, multiple stages of purification due to the formation of undesired impurities and the use of excess solvents.

In another alternative embodiment of the present invention, the crystallization process is a continuous process at a commercial scale that is both economical and safe to the environment.

In a final embodiment of the present invention, the crystallization process yields a product that is used in pharmaceutical formulation.
TABLES & DRAWINGS:
Figure 1: Describes the input properties and process parameter that attributes and further influences the crystallization process
Figure 2: Explains the sequence of nucleation and crystal growth of Guaifenesin over a period of time.
Figure 3: Shows the sequence of nucleation and crystal growth Vs. time and temperature.
Figure 4: Crystallization Apparatus.
Table 1: Shows different factors and levels of operating parameters of utilities.
Table 2: Describes the Heat liberation during nuclei formation and crystal growth.

DETAILED DESCRIPTION
The present invention relates to the improved process to yield Guaifenesin (I) with a controlled particle size distribution and an improved purity profile.

Crystal or particle size distribution is influenced by a number of variables which can be optimized and controlled during crystallization development and manufacturing. In turn, crystal size distribution influences both product and process performance as described in Figure 2 which explains the sequence of nucleation and crystal growth of Guaifenesin over a period of time, Figure 3 that shows the sequence of nucleation and crystal growth Vs. time and temperature and Figure 1 which describes the input properties and process parameter that attributes and further influences the crystallization process.

The present invention has utilized all the possible critical attributes which further influences the crystallization process and used parameters to control the Particle size and its distribution using the apparatus described in Figure 4.

The crystallization process involve the use of heat liberation, wherein the process comprises of the purification of the crude Guaifenesin to yield pure oil of Guaifenesin, which is further dissolved in solvent(s) at elevated temperature with the aid of a crystallization apparatus (A) such as a crystallizer or a reactor.

Figure 4 describes the Crystallization apparatus (A) and wherein Cylinder with tori shaped dishes at both ends (H); Hallow jacket (J) comprising of an inlet (F) and outlet (G) used to transfer cooling fluids; Control system (E); Motor (B) comprising of an agitator with half gated anchors with baffles (I); Feed line (C) and Temperature probes (D).

The apparatus is herein described in Figure 4 also comprises of a cylinder with tori shaped dishes at both ends (H), a hallow jacket (J) comprising of an inlet (F) and outlet (G) used to transfer cooling fluids, a control system (E), a motor (B) comprising of an agitator (I) with half gated anchors with baffles, a feed line (C) and temperature probes (D). During the process Guaifenesin’s crystal growth is achieved by slowly reducing the temperature over the period of time at defined rate (dt/T). The apparatus used for crystallization such as a batch reactor is driven by an electric motor (B) attached to an agitator (I) with a half gated anchor with baffles & hallow jacketed (J). The orientation of crystallizer is vertical with tori spherical dish ends (H). One end is coupled with agitator (I) and other end is coupled with blow down valve. The RPM of agitator (I) is 0-48 with adjustable frequency controller (E). There are multiple flange entries that are connected with tori spherical dish ends to ease the crystallization process i.e. temperature sensing (D), Anti solvent addition and nitrogen blanketing. The data logger such as RADIX is connected with temperature sensor (D) continuously gathers the temperature ramp across the crystallisation process. The data also gets stored at a designated place. Then the collected data is run through MINITAB statistical software using Regression co relations model to find the correlations of operating parameters vs. particle size distribution and to optimise the desired operating parameters.

The distilled pure Guaifenesin oil is crystallized in a mixture of solvent(s) such as toluene and isopropyl alcohol to obtain the specific particle size. Once the pure Guaifenesin pure oil is transferred into crystalliser with solvents(s), the reaction mass is heated to 65-75°C to get complete dissolution. The data logger starts collecting the ramp temperature of dissolution and ramp down temperature of cooling by cooling water, chilled water and chilled brine. The RPM also is set as per particle size distribution requirement. The mixture is then cooled with stirring, it is further observed for the heat liberation while crystallization (refer Table 2 for data) and the temperature is further gradually decreased by circulating cool to chilled water to 50-55°C with 30-45 RPM at 0.3-0.5°C/minute, the temperature of the mass is allowed raise to 53-59°C by holding the cooling water in the hollow jacket.

Gradually, cool water is circulated to decrease the temperature from 55-60°C to 35-40°C at 0.1-0.4°C/minute. The temperature is further reduced by circulating chilled water initially and it resulted in temperature decrease from 35-40°C to 20-25°C at 0.5-1.0°C/minute.

During the cooling process the nuclei starts transforming into the stages of crystal formation, the Guaifenesin crystal forms uniformly at defined rate of formation and the impurities also gets separated out of Guaifenesin with significant amount of reduction. The crystals formed are maintained in the uniform mix for a while after which the crystal mass is filtered and dried, which further enhances the loss of volatile impurities. Crystals of Guaifenesin are formed are then collected to yield a highly pure product with controlled particle size distribution and uniform crystalline nature. The final product is collected to yield a highly pure product with controlled particle size and its distribution along with uniform crystalline nature.

In an added embodiment of the present invention, the solvent(s) maybe selected form the group comprising of ester solvents such as ethyl acetate, isopropyl acetate, butyl acetate; halogenated solvents such as methylene chloride, ethylene dichloride, chloroform, chlorobenzene; nitrile solvents such as acetonitrile; alcoholic solvents such as methanol, ethanol, isopropanol, n-butanol; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone; ether solvents such as diethyl ether, diisopropylether, tetrahydrofuran and/or hydrocarbon solvents such as methyl cyclohexane, toluene, cyclohexane, n-hexane, n-heptane or water. The solvents used in the crystallization process was preferable toluene and isopropyl alcohol (99:01 v/v %).

Among all the impurities, impurity B is known to be the critical impurity that determines the purity of guaifenesin. The impurity B (ß isomer) reduces significantly by the new crystallisation process. The purity of guaifenesin is as tabulated below to identify the significant difference of impurity reductions. The following table cover the impurities profile of three batches of Guaifenesin.

S# Test Specification Purity of Guaifenesin with impurities reduction
Batch 1 Batch 2 Batch 3
1. Impurity B
(ß-Isomer) Impurity B
(NMT 0.60 %) 0.242 0.251 0.254
2. Impurity A (Guaiacol) Impurity A
(NMT 0.03 %) BDL
(DL- 0.001%) Not detected BDL
(DL- 0.01%)
3. Impurity C
(Dimer) Impurity C
(NMT 0.05 %) 0.029 0.032 0.030
4. Impurity D Impurity D
(NMT 0.05 %) 0.009 0.009 BQL
(QL- 0.006%)
5. AOI AOI
(NMT 0.05 %) 0.007 0.004 0.00
6. Total Impurities (Excluding ß-isomer and Guaiacol) Total Impurities (NMT 0.20 %) 0.05 0.04 0.05

The crystallization process of the present invention also yields an improved assay of Guaifenesin. The Assay of Guaifenesin is achieved at an average of 99.7 % against its specification limit of 98 – 102 % by USP method.

S.No
Test Specification Results
Batch 1 Batch 2 Batch 3
1 Assay as C10H14O4 98%-102% w/w on dry basis 99.3 % w/w 99.4% w/w 100.5 % w/w

The crystallization process of the present invention yields a product with the particle size distribution is not more than 380µ for D90; is not more than 130µ for D50 and is not more than 80µ for D10, within the ranges 220-380µ for D90; 70-130µ for D50; 25-80µ for D10; preferably ranging within the range 250-350µ for D90; 80-115µ for D50 and 35-50µ for D10.

EXAMPLES
Preparation of Guaifenesin (Pure Oil):
Charge water (240ml), phosphoric acid (2.5gm) and Epichlorohydrin (93gm) maintain temp at 95°C for 45 min. Charge sodium hydroxide (45gm) and guaiacol (120gm) maintain at 102°C for 2hrs. Separate the Aqueous layer organic layer and distill the solvent. Charge white oil (10gm) to organic layer, apply vacuum and raise the temperature at 120°C for 15 minutes, collect the 1st fraction; raise the vapour temperature to below 170°C and collect the 2nd fraction (pure oil) 159 g HPLC Purity 97.17%.

Crystallization of Guaifenesin:
Charge 159g of the 2nd fraction (pure oil), 350ml of Toluene and Isopropyl alcohol and cool the mass to 15-25°C. Filter the product. Yield: 115-123 g

Process for the preparation of Guaifenesin with a customized Particle size and its distribution
Example 1:
Charge 100g of the 2nd fraction (pure oil), 350ml of Toluene and Isopropyl alcohol into a crystallizer increase the temperature to 65-70°C to dissolve Guaifenesin (1); Cool the mass to by 15-25°C with 35 RPM at 0.3-0.5°C/minute. Further gradually allow for an increase in temperature by 3-5°C with cooling water held up in the jacket of the crystallizer. The temperature was gradually decreased by 15-25°C at 0.1-0.4°C/minute by circulating cool water and further decreased to 20-25°C at 0.5-1.0°C/minute by circulating chilled water. Filter the product. Yield: 129-138 g.

Example 2:
Charge 100g of the 2nd fraction (pure oil), 400ml of Toluene and Isopropyl alcohol into a crystallizer increase the temperature to 68-74°C to dissolve Guaifenesin (1); Cool the mass to by 10-15°C with 40 RPM at 0.3-0.5°C/minute. Further gradually allow for an increase in temperature by 2-4°C with cooling water held up in the jacket of the crystallizer. The temperature was gradually decreased by 10-15°C at 0.2-0.54°C/minute by circulating cool water and further decreased to 15-20°C at 0.8-1.3°C/minute by circulating chilled water. Filter the product. Yield: 110-121 g.

Example 3:
Charge 100g of the 2nd fraction (pure oil), 350ml of Toluene and Isopropyl alcohol into a crystallizer increase the temperature to 65-70°C to dissolve Guaifenesin (1); Cool the mass to by 15-25°C with 35 RPM at 0.3-0.5°C/minute. Further gradually allow for an increase in temperature by 3-5°C with cooling water held up in the jacket of the crystallizer. The temperature was gradually decreased by 15-25°C at 0.1-0.4°C/minute by circulating cool water and further decreased to 20-25°C at 0.5-1.0°C/minute by circulating chilled water. Filter the product. Yield: 120-131 g.

By following the above examples 1 to 3, the Table 1 shows the data of various batches manufactured with respect to particle size distribution and levels of operating parameters of utilities.

While the foregoing details of the present invention provides for a detailed description of the preferred embodiments of the invention, it is to be understood that the summary, description and examples are illustrative only of the core of the invention and non-limiting. Furthermore, as many changes can be made to the invention without departing from the scope of the invention, it is intended that all material contained herein be interpreted as illustrative of the invention and not in a limiting sense.