Polymorphic substance of oxycodone hydrochloride as well as preparation method and application of polymorphic substance

A technology for oxycodone hydrochloride and polymorphs, which is applied in the field of polymorphs of oxycodone hydrochloride and its preparation, can solve problems such as agglomeration, discoloration, and increased impurities, and achieve a simple preparation method , mild crystallization conditions, and excellent stability

Active Publication Date: 2022-04-05
北京华素制药股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These differences will significantly affect the stability, dissolution rate, and bioavailability of the corresponding preparations, thereby affecting the safety and effectiveness of the drug.
[0007] The currently disclosed preparation methods of oxycodone hydrochloride crystal forms either use organic solvents such as ethanol, isopropanol, butanol, dioxane, etc., or the crystallization conditions are difficult to realize industrial production
Through the investigation of commercially available oxycodone hydrochloride, it is found that its physical and chemical properties are unsatisfactory, and there are problems such as agglomeration, discoloration, and elevated impurities

Method used

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  • Polymorphic substance of oxycodone hydrochloride as well as preparation method and application of polymorphic substance
  • Polymorphic substance of oxycodone hydrochloride as well as preparation method and application of polymorphic substance
  • Polymorphic substance of oxycodone hydrochloride as well as preparation method and application of polymorphic substance

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0099] The XRPD spectrogram of the polymorphic form of oxycodone hydrochloride in embodiment 1, embodiment 2, embodiment 3 and embodiment 4 is respectively as figure 1 , Figure 8 , Figure 10 and Figure 12 As shown, the XRPD data are shown in Table 1, Table 2, Table 3 and Table 4 respectively. In order to test the stability of the polymorph, the polymorph of oxycodone hydrochloride with crystal form α in Example 1 was stored for 36 months at 25°C±2°C / 65%RH±5%. XRPD tests were conducted in 0, 6, 12, 24 and 36 months, the results are as follows Figure 6 and Figure 7 shown.

[0100] Table 1 XRPD data for polymorphs of oxycodone hydrochloride with Form α

[0101] serial number Signal peak number 2θ[°] D value (Angstrom) Relative Strength(%) 1 3 6.50 13.58 11.2 2 4 7.88 11.22 100.0 3 5 10.40 8.50 16.0 4 7 11.18 7.91 27.1 5 8 11.94 7.41 75.9 6 9 13.10 6.76 20.0 7 15 16.23 5.46 69.2 8 17 18.10 ...

Embodiment 2

[0172] Example 2: Preparation of Oxycodone Hydrochloride Polymorphs with Crystal Form β

[0173] Take 0.5 g of the polymorph obtained in Example 1 and spread it on a watch glass with a thickness of 1 mm, and place it in an environment with a temperature of 10-30° C. and a humidity of 70%-80% for 4 hours to obtain needle-shaped crystals.

[0174] Tested by XRPD, the results are as follows Figure 8 As shown, it was determined to be the crystal form β.

[0175] After thermogravimetric analysis, the results were as follows Figure 9 As shown, under the set test conditions, the weight loss of the sample presents two stages: the initial temperature of the first stage is about 80°C, and the weight loss of this stage ends at about 160°C, and the weight loss rate is 10.17%. This stage is caused by endothermic Water volatilizes and loses weight; the initial temperature of the second stage is about 160°C, and it loses weight rapidly as the temperature increases, and ends at about 320°...

Embodiment 3

[0176] Example 3: Preparation of Oxycodone Hydrochloride Polymorphs with Form γ

[0177] Take 0.5 g of the polymorph obtained in Example 1 and spread it on a watch glass with a thickness of 1 mm, place it in a decompression drying oven with a pressure of 0.08-0.1 MPa, and dry it for 4 hours at a temperature of 85-95 ° C to obtain Dark white powdery crystals.

[0178] Tested by XRPD, the results are as follows Figure 10 As shown, it was determined to be the crystal form γ.

[0179] After thermogravimetric analysis, the results were as follows Figure 11As shown, under the set test conditions, the weight loss of the sample presents three stages: the initial temperature of the first stage is about 200°C, and the weight loss is rapid as the temperature rises, and the weight loss rate is 43.21% at about 275°C; The second stage continues to lose weight rapidly, and the weight loss rate is 38.75% at about 345 °C; the third stage becomes gentle with the increase of temperature, an...

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Abstract

The invention relates to the field of medicines, in particular to a polymorphic substance of oxycodone hydrochloride as well as a preparation method and application of the polymorphic substance. The oxycodone hydrochloride polymorphic substance provided by the invention has the following crystal forms: crystal forms alpha, beta, gamma or delta, the polymorphic substance with the crystal forms alpha and delta can be obtained by volatilizing a solvent at a constant temperature, and the polymorphic substance with the crystal forms beta and gamma can be obtained by performing crystal transformation on the polymorphic substance with the crystal form alpha under a high-humidity or high-temperature condition. The oxycodone hydrochloride polymorphic substance obtained by the invention is relatively high in purity and excellent in stability, the preparation method is simple, the working time is short, the crystallization condition is mild, the used reagent is cheap and easy to obtain, the cost is low, and the oxycodone hydrochloride polymorphic substance is suitable for industrial production and preparation of related pharmaceutical preparations.

Description

technical field [0001] The invention relates to the field of medicine, in particular to polymorphs of oxycodone hydrochloride, a preparation method and application thereof. Background technique [0002] Oxycodone (Oxycodone) is a semi-synthetic opioid receptor agonist. Its pharmacological action and mechanism are similar to morphine. It mainly plays an analgesic effect by exciting the opioid receptors in the central nervous system. It is clinically used to relieve persistent pain. For moderate to severe pain, its analgesic effect has no capping effect, and it belongs to narcotic analgesic drugs. Oxycodone is widely used clinically because of its high bioavailability and multiple routes of administration. [0003] Oxycodone hydrochloride is the pharmaceutical raw material of oxycodone, used in oxycodone hydrochloride sustained-release tablets, oxycodone hydrochloride injection and oxycodone paracetamol. The structural formula of oxycodone hydrochloride is: [0004] [0...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D489/08A61K31/485A61P25/04
Inventor 刘攀峰董国明贾启燕房雪松魏淑冬姚文静史晓蒙李晓荣
Owner 北京华素制药股份有限公司
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