CA1131245A - Freeze dried pharmaceuticals - Google Patents
Freeze dried pharmaceuticalsInfo
- Publication number
- CA1131245A CA1131245A CA307,268A CA307268A CA1131245A CA 1131245 A CA1131245 A CA 1131245A CA 307268 A CA307268 A CA 307268A CA 1131245 A CA1131245 A CA 1131245A
- Authority
- CA
- Canada
- Prior art keywords
- water
- salt
- hydrolysis
- freeze
- soluble
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Abstract of the Disclosure Process for preparing Aspirin salts having improved stability and compositions containing same.
Description
~3~Z4~
FREEZE-DRIED PHARMACEUTICALS
This invention pertains to improved pharmaceu-tical preparations and processes for making same. In a specific embodiment, this invention also pertains to aspirin salts (salts of acetylsalicylic acid) and processes for producing them.
Aspirin salts are known to produce reduced ir-ritation of the stomach lining. Previous attempts to pro-duce an aspirin salt with satisfactory stability have been unsuccessful because of the tendency to form hydrates which result in "built-in" instability.
I have discovered methods for producing anhydrous aspirin salts, and in addition have been able to produce these soluble salts in flavored, palatable form. ~y dis-coveries are also applicable to other pharmaceutical pro-ducts whose hydrates have limited shelf life. This in-vention also relates to flavoring other pharmaceuticals.
I will describe my process for the production of Calcium Aspirin, however, it is applicable to other salts such as Magnesium Aspirin and also to other pharmace~tical hydrates.
At the heart o~ , my discovery is the determination that Calcium Aspirin in water, after being frozen, is stable for a considerable period in the frozen state. This permits freeze-drying without substantial decomposition.
Essentially my process differs from ordinary fr~eze drying in that the frozen solution of Calcium Aspirin is freeze dried first to produce the freeze dried hydrate followed by drying the hydrale i~self. The temperature is gradually raised during the drying process to permit a satisfactory rate of drying, however, the temperature can , ~ - * Trade Mark :; :
~3~
not be elevated substantially until the aspirin salt next to the heating surfaces is dry. When the material is dry but still in partial hydrate form, the temperature may be raised to approximately 50-60C for a period to accomplish the re-moval of much of the water of hydration.
The freeze dried Calcium Aspirin at this point is a mixture of anhydrous salt mixed with some hydrate. To insure complete dehydration, I prefer to introduce a second step which utilizes much higher vacuums and cooler condenser temperatures and re~uires little or no heating.
For this second step, I provide a vacuum lower than 100 microns, preferably 10 microns or lower. This is in contrast to commercial freeze-drying in which the vacuum is 1-4 mm. Hg and is not sustained below 100 microns.
In order to achieve this high vacuum in the freeze drying process, it is important to maintain the condenser temperature lower than -50C and preferably lower than -75 or lower. Under some circumstances it ls possible to use a fresh condenser without disturbing the contents in the chamber used for the first'stage.
EXAMPL~ 1. ' Anhydrous Calcium Aspirin. The pro-duct made by reaction of Aspirin and Calcium Carbonate in water, filtering, freezing, grinding the material in a room at approximately -40, placing on txays in the freeze drying chamber, applying vacuum of at least 1 mm Hg. and condensing the water on a condesner at about -40. The plates are ~arm~d raising the temperature gradually as freeze drying continues, starting so that the temperature of the dried granules do not exceed that of room temperature, and reaching at the end not above 40-50C.
When the gr~nules are dry and contain at most ~3~Z~i . .
some water of hydration, the condenser is removed and a new condenser assembly is attached capable of lower tempera-tures. ~nother vacuum pump is used which produces a vacuum o~ less than 100 microns and preferably about 1 micron. The condenser temperature should be maintained at -50 to -100C.
or lower. The granules may be warmed to keep them at room temperature or above and may be warmed to 40-50C. toward t he end of the cycle.
Calcium Aspirin made using the above procedure is shown to contain less than 0.1 mol of water of hydration and usually contains less than 0.02 mols. This is confirmed when the material is heated under vacuum in the oven at 120-130C. the weight loss resulting ~rom the formation of acetic acid (from the reaction of the aspirin with the water of hydration) is insignificant. Material made by ordinary freeze drying shows a significant weight loss under these conditions showing the presence of significant hydrate.
In performin~ the above process, I have discovered that I can use microwave heatin~ to reduce the overheating resulting from the normal heating method. This permits localizing the heating to the granules with the most water and reduces the heating of granules which are already dry.
The granules made using the above process are some-what soft. They may be used in forming tablets and can also be dissolved in water for easy swallowing. Although the taste of aspirin salts is not bad, this can be improved by flavoring. The granules may be made harder and flavor can be added prior to the freeze-drying by the addition of a soluble starch hydrolysate to the mixture prior to freezing.
Sugar or lactose may also be used in the formation. This discovery tha~ the addition of starch hydrolysate causes a harder and more stable granule and i~ addition permits the ~3~29~
addition of flavor prior to freeze drying is an important finding. It is applicable to t~e freeze drying of other soluble pharmaceuticals, but it will be described in con-nection with the preparation of the Calcium Aspirin.
Many people, including children, have difficulty swallowing tablets, and some people prefer to take their medication in liquid form. In order to prepare aspirin with a flavor that is readily soluble in water, it is important to have a product with substantial bulk so that it can be measured accurately and with a tasteful flavor.
I have shown that the addition of Maltodextrin to Methyl Salicylate solutions which are frozen and freeze dried reduces the flavor loss tremendously. I use Malto-dextrins with a dextrose equivalent (DE) of from 5 to 30 with 10 being the preferred DE. This type has a maximum stability with a minimum of lowering of freezing point.
I generally prefér a mixture prior to freeze drying which contains about 60% water and 40% solids. The solids would genexally consist of about forty to eighty percent carbohydrate, some flavor and color, and the re-mainder could be active ingredient, which in this case is Calcium Aspirin.
EXAMPLE 2. Anhydrous Magnesium Aspirin. This product is prepared following the procedure of Example 1 and substituting Magnesium Carbonate for Calcium ~arbonate.
EXAMPLE 3 . Calcium Aspirin with Maltodextrins.
Six grams of Aspirin were stirred with 3 grams of calcium carbonate added in portions to 300 ccs of water (at 10C~.
~hree grams of spray dried 20% USP Lemon Flavor, 30 grams of sugar and 44 grams of DE10 Maltodextrin are added. The mixture is filtered, frozen, and freeze dried as in the J * ~rQ ~ ~a~k ~13~5 ,, example 1 given above. The resulting product are hard granules, readily water soluble, with a good flavor.
When Calcium Aspirin is administered orally to rats in large doses, gastrointestinal bleeding may be observed upon disection. Despite the fact that the aspirin is already neutral, I have discovered that the addition of an excess of bicarbonate salt reduces this bleeding considerably and often prevents it. I use at least one part bicarbonate however greater excesses are ~ery desirable. The amoun~ of bicarbonate is even greater when acid aspirin is used. In-stead of bicarbonate, a carbonate such as calcium carbonate may also be used since it is the bicarbonate ion which ap-pears to reduce the to~icity of the salicylate ion. I have also established that other aromatic carboxylic acids show similar detoxification with bicarbonate ion. This refers to benzoate, salicylate and their deriva~ives.
A~pirin salt prepared according to this invention may be used for achieving this saer form of aspirin. The Calcium saltj as an example, can he enteric coated so that it utilizes the bicarbonate in the duodenum and bipasses the stomach. -It may also be combined ~ith calcium carbonate in a similar dosage form with or without enteric coating.
The aspirin salt ma~ be freeze dried using the above technology with bicarbonate or carbonate since I have discovered that bicarbonates such as sodium bicarbonate may be freeze dried. Calcium carbonate has the advantage that it does not lower the freezing point as does the sodium bicarbonate.
FREEZE-DRIED PHARMACEUTICALS
This invention pertains to improved pharmaceu-tical preparations and processes for making same. In a specific embodiment, this invention also pertains to aspirin salts (salts of acetylsalicylic acid) and processes for producing them.
Aspirin salts are known to produce reduced ir-ritation of the stomach lining. Previous attempts to pro-duce an aspirin salt with satisfactory stability have been unsuccessful because of the tendency to form hydrates which result in "built-in" instability.
I have discovered methods for producing anhydrous aspirin salts, and in addition have been able to produce these soluble salts in flavored, palatable form. ~y dis-coveries are also applicable to other pharmaceutical pro-ducts whose hydrates have limited shelf life. This in-vention also relates to flavoring other pharmaceuticals.
I will describe my process for the production of Calcium Aspirin, however, it is applicable to other salts such as Magnesium Aspirin and also to other pharmace~tical hydrates.
At the heart o~ , my discovery is the determination that Calcium Aspirin in water, after being frozen, is stable for a considerable period in the frozen state. This permits freeze-drying without substantial decomposition.
Essentially my process differs from ordinary fr~eze drying in that the frozen solution of Calcium Aspirin is freeze dried first to produce the freeze dried hydrate followed by drying the hydrale i~self. The temperature is gradually raised during the drying process to permit a satisfactory rate of drying, however, the temperature can , ~ - * Trade Mark :; :
~3~
not be elevated substantially until the aspirin salt next to the heating surfaces is dry. When the material is dry but still in partial hydrate form, the temperature may be raised to approximately 50-60C for a period to accomplish the re-moval of much of the water of hydration.
The freeze dried Calcium Aspirin at this point is a mixture of anhydrous salt mixed with some hydrate. To insure complete dehydration, I prefer to introduce a second step which utilizes much higher vacuums and cooler condenser temperatures and re~uires little or no heating.
For this second step, I provide a vacuum lower than 100 microns, preferably 10 microns or lower. This is in contrast to commercial freeze-drying in which the vacuum is 1-4 mm. Hg and is not sustained below 100 microns.
In order to achieve this high vacuum in the freeze drying process, it is important to maintain the condenser temperature lower than -50C and preferably lower than -75 or lower. Under some circumstances it ls possible to use a fresh condenser without disturbing the contents in the chamber used for the first'stage.
EXAMPL~ 1. ' Anhydrous Calcium Aspirin. The pro-duct made by reaction of Aspirin and Calcium Carbonate in water, filtering, freezing, grinding the material in a room at approximately -40, placing on txays in the freeze drying chamber, applying vacuum of at least 1 mm Hg. and condensing the water on a condesner at about -40. The plates are ~arm~d raising the temperature gradually as freeze drying continues, starting so that the temperature of the dried granules do not exceed that of room temperature, and reaching at the end not above 40-50C.
When the gr~nules are dry and contain at most ~3~Z~i . .
some water of hydration, the condenser is removed and a new condenser assembly is attached capable of lower tempera-tures. ~nother vacuum pump is used which produces a vacuum o~ less than 100 microns and preferably about 1 micron. The condenser temperature should be maintained at -50 to -100C.
or lower. The granules may be warmed to keep them at room temperature or above and may be warmed to 40-50C. toward t he end of the cycle.
Calcium Aspirin made using the above procedure is shown to contain less than 0.1 mol of water of hydration and usually contains less than 0.02 mols. This is confirmed when the material is heated under vacuum in the oven at 120-130C. the weight loss resulting ~rom the formation of acetic acid (from the reaction of the aspirin with the water of hydration) is insignificant. Material made by ordinary freeze drying shows a significant weight loss under these conditions showing the presence of significant hydrate.
In performin~ the above process, I have discovered that I can use microwave heatin~ to reduce the overheating resulting from the normal heating method. This permits localizing the heating to the granules with the most water and reduces the heating of granules which are already dry.
The granules made using the above process are some-what soft. They may be used in forming tablets and can also be dissolved in water for easy swallowing. Although the taste of aspirin salts is not bad, this can be improved by flavoring. The granules may be made harder and flavor can be added prior to the freeze-drying by the addition of a soluble starch hydrolysate to the mixture prior to freezing.
Sugar or lactose may also be used in the formation. This discovery tha~ the addition of starch hydrolysate causes a harder and more stable granule and i~ addition permits the ~3~29~
addition of flavor prior to freeze drying is an important finding. It is applicable to t~e freeze drying of other soluble pharmaceuticals, but it will be described in con-nection with the preparation of the Calcium Aspirin.
Many people, including children, have difficulty swallowing tablets, and some people prefer to take their medication in liquid form. In order to prepare aspirin with a flavor that is readily soluble in water, it is important to have a product with substantial bulk so that it can be measured accurately and with a tasteful flavor.
I have shown that the addition of Maltodextrin to Methyl Salicylate solutions which are frozen and freeze dried reduces the flavor loss tremendously. I use Malto-dextrins with a dextrose equivalent (DE) of from 5 to 30 with 10 being the preferred DE. This type has a maximum stability with a minimum of lowering of freezing point.
I generally prefér a mixture prior to freeze drying which contains about 60% water and 40% solids. The solids would genexally consist of about forty to eighty percent carbohydrate, some flavor and color, and the re-mainder could be active ingredient, which in this case is Calcium Aspirin.
EXAMPLE 2. Anhydrous Magnesium Aspirin. This product is prepared following the procedure of Example 1 and substituting Magnesium Carbonate for Calcium ~arbonate.
EXAMPLE 3 . Calcium Aspirin with Maltodextrins.
Six grams of Aspirin were stirred with 3 grams of calcium carbonate added in portions to 300 ccs of water (at 10C~.
~hree grams of spray dried 20% USP Lemon Flavor, 30 grams of sugar and 44 grams of DE10 Maltodextrin are added. The mixture is filtered, frozen, and freeze dried as in the J * ~rQ ~ ~a~k ~13~5 ,, example 1 given above. The resulting product are hard granules, readily water soluble, with a good flavor.
When Calcium Aspirin is administered orally to rats in large doses, gastrointestinal bleeding may be observed upon disection. Despite the fact that the aspirin is already neutral, I have discovered that the addition of an excess of bicarbonate salt reduces this bleeding considerably and often prevents it. I use at least one part bicarbonate however greater excesses are ~ery desirable. The amoun~ of bicarbonate is even greater when acid aspirin is used. In-stead of bicarbonate, a carbonate such as calcium carbonate may also be used since it is the bicarbonate ion which ap-pears to reduce the to~icity of the salicylate ion. I have also established that other aromatic carboxylic acids show similar detoxification with bicarbonate ion. This refers to benzoate, salicylate and their deriva~ives.
A~pirin salt prepared according to this invention may be used for achieving this saer form of aspirin. The Calcium saltj as an example, can he enteric coated so that it utilizes the bicarbonate in the duodenum and bipasses the stomach. -It may also be combined ~ith calcium carbonate in a similar dosage form with or without enteric coating.
The aspirin salt ma~ be freeze dried using the above technology with bicarbonate or carbonate since I have discovered that bicarbonates such as sodium bicarbonate may be freeze dried. Calcium carbonate has the advantage that it does not lower the freezing point as does the sodium bicarbonate.
Claims (5)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process of preparing a water-soluble, substantially anhydrous material stable to hydrolysis comprising subjecting a freeze-dried, water-soluble material containing molecularly bound water and which is susceptible to hydrolysis to a vacuum of 10 microns or less Hg to remove said molecularly bound water and condensing the removed water on a condenser below -50°C.
2. A process of preparing water-soluble, substantially anhydrous salt of acetylsalicylic acid stable to hydrolysis comprising subjecting a frozen aqueous solution of a salt of acetylsalicylic acid to freeze drying at a temperature of about - 20° to about - 40°C under a vacuum of about 1 to about 0.1 microns Hg to provide a freeze dried salt of acetylsalicylic acid containing molecularly bound water which is susceptible to hydrolysis, subjecting said freeze-dried salt to a second freeze drying at a vacuum of 10 microns or less Hg to remove molecularly bound water and condensing said water on a condenser below - 50°C.
3. The process of claim 4 wherein the salt of acetyl-salicylic acid is a calcium salt of acetylsalicylic acid.
4. A water-soluble, substantially anhydrous pharmaceuti-cal salt of acetylsalicylic acid stable to hydrolysis, when prepared by the process of any one of claims 1, 2 or 3 or by their obvious chemical equivalents.
5. A water-soluble, substantially anhydrous calcium salt of acetylsalicylic acid stable to hydrolysis, when prepared by the process of any one of claims 1, 2 or 3 or by their obvious chemical equivalents.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA307,268A CA1131245A (en) | 1978-07-12 | 1978-07-12 | Freeze dried pharmaceuticals |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA307,268A CA1131245A (en) | 1978-07-12 | 1978-07-12 | Freeze dried pharmaceuticals |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1131245A true CA1131245A (en) | 1982-09-07 |
Family
ID=4111893
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA307,268A Expired CA1131245A (en) | 1978-07-12 | 1978-07-12 | Freeze dried pharmaceuticals |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1131245A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11911400B1 (en) | 2017-05-30 | 2024-02-27 | Rhoshan Pharmaceuticals, Inc. | In-vial deposition of a stable, sterile and crystalline O-acetyl salicylic acid (aspirin) |
-
1978
- 1978-07-12 CA CA307,268A patent/CA1131245A/en not_active Expired
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11911400B1 (en) | 2017-05-30 | 2024-02-27 | Rhoshan Pharmaceuticals, Inc. | In-vial deposition of a stable, sterile and crystalline O-acetyl salicylic acid (aspirin) |
| US12048708B2 (en) | 2017-05-30 | 2024-07-30 | Rhoshan Pharmaceuticals, Inc. | In-vial deposition of a stable, sterile and crystalline o-acetyl salicylic acid (aspirin) |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |