MXPA01010649A - Haze-free cellulose ether capsules and process for making - Google Patents

Abstract

Disclosed is a cellulose ether composition having a low molecular weight cellulose ether of a viscosity of about 200 mPas or less in a two percent aqueous solution at 20°C. The composition has a sodium chloride content of about 0.3 weight percent or less based upon the weight of the cellulose ether. The composition exhibits significantly reduced haze formation when in capsule form. Also disclosed is a process for making the composition.

Description

ULAS CELLS OF ETHER OF CE LULOSA FREE OF NEBLI NA AND PROCESS TO PREPARE THEM The present invention relates to mist-free cellulose ether capsules and a process for making them. The capsules are useful in pharmaceutical applications. Cellulose ethers are commonly used commercially to form capsules that are adapted to contain and orally deliver pharmaceutical agents and medicaments. The preferred cellulose ethers for such applications are methylcellulose and hydroxypropylmethylcellulose. Cellulose ether capsules are typically made by immersing hot pins in an aqueous, cold cellulose ether dip coating solution. The solution is set in the pins and the water is evaporated during a drying step to form thin film layers of dry cellulose ether around the hot pins. Thin films take the form of layers and bodies, which are thus removed from the pins. The layers are matched with bodies to form the capsules. There are analogous processes in which the cold pins are immersed in a hot, aqueous cellulose ether solution. The processes for making the capsules are observed in the US Patents. Nos. 3.61, 7,588; 4,001, 21 1; 4, 917,885 and 5,756,036. A problem commonly encountered in the manufacture of cellulose ether capsules is the formation of haze on their internal surfaces. The formation of haze is the most distinguishable in transparent capsules. The mist causes the cellulose ether capsules to show less luster and shine than they would otherwise have. Due to the haze, cellulose ether capsules typically do not have the same level of luster as gelatin capsules. This difference in appearance is discussed in "HPMC Capsules - An Alternative to Gelatin", Pharmaceutical Technology Europe 1 0 (1 1 998). It would be desirable to have cellulose ether capsules that are substantially free of the formation of haze on their internal surfaces and a process for making such capsules. It would also be desirable to have a process for making a cellulose ether composition useful in such capsules. According to the present invention, there is a cellulose ether composition comprising a low molecular weight cellulose ether. The composition has a sodium chloride content of about 0.3 weight percent or less based on the weight of the cellulose ether. The composition shows significantly reduced haze formation when it is in the form of a capsule. Useful embodiments also include capsule and aqueous forms of the composition. More in accordance with the present invention, there is a process for making a cellulose ether composition. The process comprises a) alkalizing a pulp of cellulose by contacting it with sodium hydroxide; b) etherifying the cellulose pulp to form a cellulose ether; c) washing the cellulose ether to reduce the sodium chloride content; d) drying the cellulose ether at a reduced moisture content; e) grinding the cellulose ether in a particle form; f) contacting the particulate cellulose ether with a sufficient amount of hydrogen chloride to sufficiently depolymerize it so that an aqueous solution of two percent of it has a viscosity of 200 cP or less at 20 ° C; g) neutralizing partially or substantially neutralizing the acid by contacting with a sodium compound. The cellulose ether is washed to a sufficient degree and the amount of hydrogen chloride employed is adjusted to a sufficient degree to limit the sodium chloride content of the depolymerized cellulose ether to about 0.3 weight percent or less based on weight of depolymerized cellulose ether. Further according to the present invention, there is a process for making the cellulose ether capsules of the cellulose ether composition having low sodium chloride content. The cellulose ether is dissolved in water to form a dip coating solution. The metal pins are immersed in the coating solution. The solution is allowed to curdle and subsequently dry on the pins to form thin films of dry cellulose ether around the pins. The thin films take the form of layers and / or bodies which are thus removed from the pins. The layers and / or bodies that subsequently can be matched to form the complete capsules. The processes of both the cold solution / hot pin and the hot solution / cold pin, they are contemplated.

In the present invention, it was found that the formation of haze in cellulose ether capsules can be significantly reduced by limiting the amount of sodium chloride remaining in the depolymerized end product from which the capsules are formed. The amount of sodium chloride remaining in the final product can be controlled by the following two methods: i) washing the cellulose ether following the etherification and before grinding to reduce the sodium chloride content and ii) limiting the amount of chloride of hydrogen used in the depolymerized reactor to limit and preferably minimize the amount of the sodium chloride derivative produced. Sub-steps i) and ii) are used to a sufficient degree to reduce the sodium chloride content of the final product of depolymerized cellulose ether to about 0.3 weight percent or less and more preferably about 0.15 weight percent or less in based on the weight of the depolymerized cellulose ether. Generally, low molecular weight cellulose ethers are produced by alkalizing or causticizing a cellulose pulp and etherifying it to form a high molecular weight cellulose ether, which is thus depolymerized to form a low molecular weight cellulose ether. The high molecular weight cellulose ethers have viscosities of up to about 100,000 standard units of viscosity (cP) in a 2 percent aqueous solution at 20 ° C. The low molecular weight cellulose ethers have viscosities of about 200 cP or less in a 2 percent aqueous solution at 20 ° C. The viscosities are determined according to ASTM D1347 in the case of methylcellulose and according to ASTM D2363 in the case of hydroxypropylmethylcellulose. 1 standard unit of viscosity (cP) corresponds to 1 mPa's. The cellulose pulp is alkalized or causticized in a reactor with an alkali hydroxide, preferably sodium hydroxide. The pulp can be alkalized by any means known in the art, such as soaking in a bath or stirred tank or by spraying directly into the dried pulp. The headspace of the reactor can be evacuated or purified with an inert gas to control the depolymerization of the cellulose ether product. The alkylated cellulose pulp is thus etherified to form the cellulose ethers of preferably up to about 100,000 cP in a 2 percent solution at 20 ° C. Typical etherifying agents include lower alkyl halides such as methyl chloride and ethyl chloride and epoxides such as ethylene oxide, propylene oxide, and butylene oxide. For example, methyl chloride can be used to make the methylcellulose and a mixture of methyl chloride and propylene oxide can be used to make the hydroxypropylmethylcellulose. The use of methyl chloride with sodium hydroxide such as an alkalizing agent results in the formation of the sodium chloride (salt) derivative. If desired, a diluent such as dimethyl ether may be employed during the etherification. The cellulose ether is washed to remove the salt and other reaction derivatives. The washing is employed together with the control of the amount of hydrogen chloride used in the depolymerization reaction (see below) to minimize the residual salt content in the final product of depolymerized cellulose ether. Any solvent in which the salt is soluble may be employed, but water is highly preferred. The cellulose ether can be washed in the etherification reactor but is preferably washed in a separate scrubber located downstream of that reactor. The process washing variables that impact the residual salt content in the cellulose ether include wash time, salt content of the wash solvent (water), and multiple washings. Residual salt content is controlled more effectively by multiple washes, being sufficient usually with two separate washes. Before or after washing, the cellulose ether can be distilled by exposure to steam to further reduce the residual organic content. The washed cellulose ether is thus dried at a reduced moisture content of 0.5 to 5.0 weight percent water and preferably 0.8 to 3.0 weight percent water based on the weight of the cellulose ether. Useful dryers include tray dehydrators, fluid layer dryers, instant dryers, shake dryers, and duct dryers. The cellulose ether is ground into particles of desired size. If desired, the cellulose ether can be ground and dried simultaneously. The grinding can be accomplished by any means known in the art such as a ball grinder or impact pulverizer. The molten particles of high molecular weight cellulose ether are de-polymerized to form low molecular weight cellulose ethers into particles. The depolymerized low molecular weight cellulose ethers typically have molecular weights, such that a two percent aqueous solution at 20 ° C has a viscosity of about 200 cP or less, preferably 1 to 1 00 cP, and more preferably 3. at 100 cP. The cellulose ethers usually used in the manufacture of pharmaceutical capsules and coatings have viscosities of 3 to 1.5 cP in a two percent aqueous solution at 20 ° C. In preparation for depolymerization, the cellulose ether particles are heated at a temperature of 50 ° C to 1 30 ° C and preferably 60 ° C to 100 ° C. The heating can be achieved in the depolymerization reactor or by a separate heater upstream of such a reactor. The moisture content of the particles can be restored, if necessary, to a higher level prior to depolymerization by mixing the particles with water in the depolymerization reactor or a separate mixer upstream of such a reactor. The ground cellulose ether particles are depolymerized by contacting or treating them with a strong acid, preferably anhydrous hydrogen chloride. The acid can be added to the headspace of the reactor or directly to the cellulose ether powder. The head space of the reactor can be distilled with an inert gas to prevent combustion or ignition of the powder. Following depolymerization, the particulate cellulose ether is contacted with a basic sodium compound, preferably a substantially anhydrous compound such as sodium bicarbonate, to partially or substantially neutralize any remaining acid. A preferred method of neutralization is to inject air into the compound in the headspace or interior of the depolymerization reactor or other container in which the depolymerized particulate cellulose ether can be adapted. The depolymerization reactor or other container loses stability preferably during neutralization to ensure uniform contact with the internal surfaces of the reactor. To minimize or limit the amount of the sodium chloride derivative produced during neutralization, the amount (concentration) of hydrogen chloride used to catalyze the depolymerization reaction is set at relatively low levels and is preferably minimized. The amount (concentration) of hydrogen chloride and the reaction temperature substantially govern the reaction rate. The losses in the reaction rate due to the reduction in the amount of hydrogen chloride used can be compensated for by increasing the reaction temperature or by increasing the reaction time. Since increases in reaction time, reduce production efficiencies and reach economic costs, it is more desirable to increase the reaction temperatures for processing by relatively lower amounts of sodium chloride. Conventionally, the depolymerization reaction temperatures have varied from 50 ° C to 1 30 ° C and more typically from 60 ° C to 100 ° C. To increase the reaction time, higher reaction temperatures of 80 ° C to 1 10 ° C are most preferred in the present invention. In a preferred embodiment, the hydrogen chloride is added to the depolymerization reactor at 0.1 to 0.19 weight percent based on the weight of the cellulose ether to be depolymerized. The teachings useful in relation to the manufacture of low molecular weight cellulose ethers are observed in the E. U. Serial No. 09 / 203,324, filed on December 1, 1998, equivalent to WO 00/32637 A1 published, in the Patent of E. U. No. 3,391, 1 35 and in the European Patent Specification EP 0 21 0 91 7. The present process is useful for making the following cellulose ethers: methylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, and hydroxybutylmethylcellulose. The process is particularly useful in the preparation of methylcellulose and hydroxypropylmethylcellulose. The low molecular weight cellulose ethers are useful in other pharmaceutical applications such as tablet coatings and such as excipients for pharmaceutical agents and drugs in capsules and tablets. Other useful applications include processing products and food products. While the modalities of the process for capsule and process of the present invention have been shown with respect to the specific details, it will be appreciated that the present invention can be modified while still being almost within the scope of the teachings and novel established principles (as) in the present.

Claims (12)

1. CLAIMS 1. A cellulose ether composition in the form of a capsule comprising a low molecular weight cellulose ether having a viscosity of 200 mPa's or less in a two percent aqueous solution at 20 ° C, the composition having a content of sodium chloride 0.3 percent by weight or less based on the weight of the cellulose ether.
2. 2. The composition according to claim 1, having a sodium chloride content of 0.1-5 weight percent or less based on the weight of the cellulose ether.
3. 3. The composition according to claim 1 or claim 2, comprising the cellulose ether methylcellulose or hydroxypropylmethylcellulose.
4. 4. The composition according to any of claims 1 to 3, characterized in that the viscosity of the cellulose ether is 3 to 1 00 mPa's.
5. 5. The composition according to claims 1 to 4, characterized in that the viscosity of the cellulose ether is from 3 to 15 mPa's.
6. 6. A process for making the cellulose ether composition, the process comprising: a) alkalizing a cellulose pulp by contacting it with sodium hydroxide; b) etherifying a cellulose pulp to form a cellulose ether; c) washing the cellulose ether to reduce the sodium chloride content; d) drying the cellulose ether at a reduced moisture content; e) grinding the cellulose ether in a particulate form; f) contacting the particulate cellulose ether with a sufficient amount of hydrogen chloride to partially depolymerize it in such a way that an aqueous solution of two percent thereof has a viscosity of 200 mPa's or less at 20 ° C. g) partially or substantially neutralizing the hydrogen chloride by contacting the particulate cellulose ether with a basic sodium compound, washing the cellulose ether in step c) to a degree and adjusting the amount of hydrogen chloride in the step f) to a degree sufficient to limit the sodium chloride content of the depolymerized cellulose ether to 0.3 weight percent or less based on the weight of the depolymerized cellulose ether.
7. The process according to claim 6, characterized in that the depolymerized cellulose ether is dissolved in water to form a coating solution by immersion, the metal pins being immersed in the coating solution, the metal pins being removed from the coating solution, allowing the solution for curing and subsequently drying on the surface of the pins to form layers and / or bodies, and removing the layers and / or bodies of the pins.
8. 8. The process according to claim 6 or 7, characterized in that the sodium compound is sodium bicarbonate.
9. 9. The process according to any of claims 6 to 8, characterized in that the cellulose ether is a methylcellulose or a hydroxypropylmethylcellulose.
10. 10. The process according to any of claims 6 to 9, characterized in that the particulate cellulose ether is depolymerized at a temperature of 50 ° C to 130 ° C. eleven .
11. The process according to claim 10, characterized in that the particulate cellulose ether is depolymerized at a temperature of 80 ° C to 1 10 ° C.
12. 12. The process according to any of claims 6 to 11, characterized in that the amount of hydrogen chloride used is 0.10 to 0.19 weight percent based on the weight of the cellulose ether.