FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"One step micronisation cum sterilization of steroids through spray drying
methodology"
2. APPLICANT:
(a) NAME: SYMBIOTEC PHARMALAB PRIVATE LIMITED
(b) NATIONALITY: Indian Company incorporated under the Indian
Companies ACT, 1956
(c) ADDRESS: 385/2, A. B. Road, Pigdamber - Rau, Indore 453 446
Madhya Pradesh, India
3.PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be performed
GRANTED

Technical field of the invention:
This invention relates to single step crystallization, micronisation cum sterilization of active pharmaceutical ingredients (APIs) by spray drying technique to obtain APIs with a high degree of assurance of sterility. More particularly, this invention relates to achieving sterility through spray drying with micronisation for steroids / steroidal hormones and their derivatives. Substantial economic benefits are derived from this invention.
Background and prior art:
Sterile APIs are raw materials for various pharmaceutical compositions such as injections, including suspension like formulations and ophthalmic preparations amongst others. Sterile APIs have to comply with various quality parameters as any non-sterile API. In addition, specific requirements for materials to be processed as sterile dosage forms include particle size, specifically in suspension type formulations and sterility, especially where the formulation cannot be or not allowed to be terminally sterilized.
The current method of manufacturing sterile APIs includes the following processes:
a) Crystallisation of finished API in general non-aseptic environment;
Micronisation of crystallized API in microniser / Jet mill to required particle size in non
aseptic environment.
Sterilization of micronised API done by gas sterilization,using Ethylene oxide as gas / Gamma Radiation in Government approved laboratory.
b) The processes of crystallization, micronisation and sterilisation are unit processes, one
followed by the other, requiring individual equipments. In the case of sterile API these
processing equipments will have to be located in clean, preferably aseptic areas to assure
sterility in the final product. Locating and operating equipments in clean or aseptic areas
will require providing clean air and other utilities such as filtered gases, sterile water to
all such areas, trained personnel to work in all such areas and continuous environmental
monitoring of such areas to ensure sterility. Further all such equipments should be
provided with CIP and SIP systems to assure sterility. Since the processes are unit

operations, one followed by the other, batch processing time is considerable. Also in the case of gas sterilisation using Ethylene oxide or gamma radiation sterilisation, the material has to sterilized in government approved laboratories only, further increasing the processing time. These are the various factors that add on to make the cost of sterile APIs considerably high.
Various equipments are available for micronisation of drugs such as ball mill, fluid-energy mill and hammer mill. Various methods of sterilisation are described in prior art. Heat sterilisation- steam and dry heat, radiation sterilization, gas sterilisation using Ethylene oxide and aseptic processing are some of the well established techniques. But no prior art has been found for a single step process for crystallization, micronisation and sterilization of APIs.
The objective of the present invention is to provide a single operation in aseptic conditions instead of three operations, for crystallization, micronisation and sterilization of API, which can give a high degree of assurance of sterility and the required particle size, thus remarkably reducing batch processing time, increasing capacities of production and providing substantial economic benefits.
Summary of the invention:
The present invention relates a single step crystallization, micronisation cum sterilization of APIs giving APIs with a high degree of assurance of sterility and required particle size. The single step processing is carried out in a spray drier fitted with the necessary pre and post 0.2 micron solution (HEPA) filters for the feed material and necessary HEPA filters for drying gas and the condensate exiting from the equipment along with the drying gas to be recycled. The spray drier equipment is suitably modified to achieve sterility.
Description of drawing:
Figure 1 shows the schematic representation of the modified spray drier comprising a feed inlet(l) passing through a HEPA filter(2), a drying chamber(3), a drying gas inlet (7) wherein the inlet gas passes through a fan(4), a heater(5) and a HEPA filter(6), discharge

port of the drying chamber connected to a powder collection cyclone(8) fitted with isolator valve (9) to collect main powder fraction into sterile vessels, the cyclone connected to a bag filter (10), also fitted with isolator valves (11), which collects the fines followed by a HEPA filter (12) and a condenser (13). The outlet of the condenser is connected to the inlet (15) of the drying gas. An outlet (14) for nitrogen is provided and the condenser has an outlet (16) for the solvent
Detailed description of the invention:
The present invention relates to a process whereby the API is crystallised, micronised and sterilised in a unit process operation. The present invention further relates to the spray drier equipment wherein the three processes of crystallization, micronisation and sterilisation are carried out resulting in a sterile, micronised API which is further used to prepare sterile formulations.
Spray drier is conventionally a pneumatic dryer which is used for the drying of powders with applications in various industries. Spray driers typically consist of a drying chamber, a feed inlet, a drying gas inlet, a solid gas separator and a dry powder product collection system (cyclone). The typical working of a spray drier consists of dispersing the solution/slurry of the material to be dried as fine droplets into a moving stream of hot gas, evaporation of the liquid resulting in fine dried powder which is collected in powder collector.
A modified spray drier of the present invention comprises a drying chamber, a feeding port fitted with high efficiency particulate air (HEPA) filter, an inlet for drying gas fitted with a fan, a heater and a HEPA filter, a powder collection cyclone connected to the discharging end of the drying chamber, a bag filter connected to the powder collection cyclone followed by a HEPA filter and a condenser comprising a discharge port connected to the drying gas inlet.
In the present invention, the spray drier's powder collection cyclone is located in an aseptic area. The material to be dried is introduced into the drying chamber through a

HEPA filter. Nitrogen as the drying gas is introduced after passing through a fan, a heater, and a HEPA filter into the drying chamber. The feed material is dried and the main powder fraction is collected in a cyclone separator. The fines are collected in a bag filter. Following the bag filter is a HEPA filter which filters the gas coming out of the bag filter. This is followed by a condenser which condenses the moisture from the Nitrogen, before it recycles as the drying gas.
The entire process is carried in aseptic condition. The material is passed into pre-cleaned and pre-sterilised closed circuit of spray drier through pre and final filters. A one step process for micronisation cum sterilization of active pharmaceutical ingredients using a modified spray drying methodology comprising the steps of;
a) preparing a solution of the active pharmaceutical ingredient in a solvent or mixtures of solvents,
b) passing the solution through pre-and final filters of 0.2 microns,
c) generating a fine spray of the solution,
d) drying the solution using a drying gas and maintaining the spray drying process parameters and
e) collecting the dried, micronised and sterilised material.
The solution of the material is prepared in solvents such as acetone, methanol, purified water and mixtures thereof. The drying gas used is Nitrogen which is recycled by passing the drying gas through HEPA filter connected to bag filter and condensing the moisture in said drying gas by passing through condenser.
The resultant material complied with quality parameters such as particle size, sterility, assay and others. The particle size range specified is: 100% should be less than 10µ and 99% should be less than less than 5µ, which is achieved by the process described above.
The process described herein is applicable to various steroids/steroidal hormones and their derivatives required for formulating sterile pharmaceutical compositions such as:

Beclomethasone Dipropionate Betamethasone Acetate Betamethasone Dipropionate Dexamethasone Dexamethasone Acetate Flumethasone Pivalate Fluticasone Propionate Hydrocortisone Acetate Medroxyprogesterone Methylprednisolone Acetate Mometasone Furoate Norethisterone Prednisolone Acetate Triamcinolone Acetonide Trimacinlone Acetonide Acetate
Preferred embodiments of the process are exemplified as follows:
Example 1:
25 gms of Triamcinolone Acetonide (TA) was dissolved in a mixture of acetone: purified water in the ratio of 552.7 gm : 50 gms respectively to obtain clear solution at 45 ° C. The clear solution was passed into pre-cleaned and pre-sterlised closed circuit spray dryer through prefilter and final filter of 0.2 micron.
The fine spray dried particles of TA were collected in pressterilized container with the help of isolation valves.
Following were the spray drying parameters maintained during trials:
Feed flow rate : 216g/Hr.
Atomisation flow rate : 2.0 Kg /Hr.

Drying gas (N2) inlet temp Drying gas (N2) outlet temp Drying gas (N2) flow rate Overall yield obtained

75 °C. 60 °C. 20 Kg / Hr. 70%

Following were the analytical results obtained of the product:

Sr.No. Test Specifications
1. Particle size 99% < 5 Microns 100%<10Microns
2. Sterility Must Comply
3. 4. Assay Specific optical As per EP/USP
rotation (SOR) As per EP/USP

Result
complies
complies complies
complies

Example 2:
40 gms of Methyl Prednisolone Acetate (MPA) was dissolved in a mixture of acetone: methanol in the ratio of 316.6 gm : 314.4 gms, almost 1:1 respectively to obtain clear solution at about 28 °C. The clear solution was passed into pre-cleaned and pre-sterilised closed circuit spray dryer through prefilter and final filter of 0.2 micron. The fine spray dried particles of MPA were collected in pre-sterilized container with the help of isolation valves.
Following were the spray drying parameter maintened duringj trials:

Feed flow rate Atomisation flow rate Drying gas (N2) inlet temp Drying gas (N2) outlet temp

205 g/Hr. 2.0 Kg /Hr. 75 °C. 59 °C.


Drying gas ( N2) flow rate : 20 Kg / Hr.
Overall yield obtained : 78%
Following were the analytical results obtained of the product:
Sr.No. Test Specifications Result
1. Particle size 99% < 5 Microns complies
100% < 10 Microns
2. Sterility Must Comply complies
3. Assay As per EP/USP complies
4. SOR As per EP/USP complies
The process of the present invention is illustrated by the abovementioned examples, which in no way limit the scope of the invention.