Stable crystals of ropivacaine

Abstract

The present disclosure relates to stable crystals of ropivacaine, which have an aspect ratio of about less than or equal to 1:1-2, a small specific surface area, a stable structure, the slowest release rate in dissolution test, and better clinical advantages.

Description

Technical Field

[0001] This disclosure relates to the pharmaceutical field, specifically to a different type of ropivacaine crystal. Background Technology

[0002] Ropivacaine is a pure levorotatory long-acting amide local anesthetic. It produces a reversible blockade of impulse conduction along nerve fibers by blocking the inflow of sodium ions into the nerve fiber cell membrane, thus having both anesthetic and analgesic effects. Clinically, high doses can be used for surgical anesthesia, while low doses produce sensory blockade (analgesia) accompanied only by localized, non-progressive motor nerve blockade.

[0003] Crystals typically exist in multiple morphologies, each with its own specific morphological characteristics, especially those related to the crystal's growth environment, conditions, or structure. Crystal habits are often used to describe certain habits or characteristics during crystal growth, involving the crystal's shape, size, symmetry, and surface features. Ropivacaine crystals are known to exist in multiple morphologies, meaning there are various ropivacaine crystal habits. Different crystal habit morphologies have different effects on formulation production and the final product, ultimately affecting drug release and efficacy. Therefore, the preparation of stable ropivacaine crystals that are easy to formulate and have good release properties has always been a pursuit of those skilled in the art. Summary of the Invention

[0004] One objective of this disclosure is to provide a ropivacaine crystal having a specific aspect ratio. In this disclosure, the aspect ratio is the ratio of the crystal's length (L) to its width (W), calculated using the following formula:

[0005] Aspect Ratio = L / W

[0006] In one technical solution of this disclosure, the aspect ratio of the ropivacaine crystal is approximately 1:(1-2).

[0007] Furthermore, the aspect ratio of the ropivacaine crystal is approximately 1:(1 to 1.9).

[0008] Furthermore, the aspect ratio of the ropivacaine crystal is approximately 1:(1 to 1.8).

[0009] Furthermore, the aspect ratio of the ropivacaine crystal is approximately 1:(1 to 1.7).

[0010] Furthermore, the aspect ratio of the ropivacaine crystal is approximately 1:(1 to 1.6).

[0011] Furthermore, the aspect ratio of the ropivacaine crystal is approximately 1:(1 to 1.5).

[0012] Furthermore, the aspect ratio of the ropivacaine crystal is approximately 1:(1 to 1.4).

[0013] Furthermore, the aspect ratio of the ropivacaine crystal is approximately 1:(1 to 1.3).

[0014] Furthermore, the aspect ratio of the ropivacaine crystal is approximately 1:(1 to 1.2).

[0015] Furthermore, the aspect ratio of the ropivacaine crystal is approximately 1:(1 to 1.1).

[0016] Furthermore, the aspect ratio of the ropivacaine crystal is approximately 1:1.

[0017] In one embodiment of this disclosure, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals have an aspect ratio of about 1:(1 to 2).

[0018] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals have an aspect ratio of about 1:(1 to 1.9).

[0019] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals have an aspect ratio of about 1:(1 to 1.8).

[0020] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals have an aspect ratio of about 1:(1 to 1.7).

[0021] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals have an aspect ratio of about 1:(1 to 1.6).

[0022] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals have an aspect ratio of about 1:(1 to 1.5).

[0023] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals have an aspect ratio of about 1:(1 to 1.4).

[0024] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals have an aspect ratio of about 1:(1 to 1.3).

[0025] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals have an aspect ratio of about 1:(1 to 1.2).

[0026] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals have an aspect ratio of about 1:(1 to 1.1).

[0027] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals have an aspect ratio of about 1:1.

[0028] Another object of this disclosure is to provide a ropivacaine crystal, wherein the ropivacaine crystal at room temperature D 50 Approximately 5-10 μm. In this disclosure, D 50 It refers to the particle size corresponding to the cumulative particle size distribution percentage of a sample reaching 50%, also called the median particle size or median particle size, and is often used to represent the average particle size of crystals.

[0029] Furthermore, the ropivacaine crystals at room temperature have a D... 50 It is approximately 5-10 μm.

[0030] Furthermore, the ropivacaine crystals at room temperature have a D... 50 Approximately 5.0μm, 5.1μm, 5.2μm, 5.3μm, 5.4μm, 5.5μm, 5.6μm, 5.7μm, 5.8μm, 5.9μm, 6.0μm, 6.1μm, 6.2 μm, 6.3μm, 6.4μm, 6.5μm, 6.6μm, 6.7μm, 6.8μm, 6.9μm, 7.0μm, 7.1μm, 7.2μm, 7.3μm, 7.4μm, 7.5 μm, 7.6μm, 7.7μm, 7.8μm, 7.9μm, 8.0μm, 8.1μm, 8.2μm, 8.3μm, 8.4μm, 8.5μm, 8.6μm, 8.7μm, 8. 8μm, 8.9μm, 9.0μm, 9.1μm, 9.2μm, 9.3μm, 9.4μm, 9.5μm, 9.6μm, 9.7μm, 9.8μm, 9.9μm, or 10.0μm,

[0031] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals contain D at room temperature. 50 It is approximately 5-10 μm.

[0032] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals contain D at room temperature.50 It is approximately 5.0 μm.

[0033] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals contain D at room temperature. 50 It is approximately 5.1 μm.

[0034] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals contain D at room temperature. 50 It is approximately 5.2 μm.

[0035] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals contain D at room temperature. 50 It is approximately 5.3 μm.

[0036] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals contain D at room temperature. 50 It is approximately 5.4 μm.

[0037] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals contain D at room temperature. 50 It is approximately 5.5 μm.

[0038] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals contain D at room temperature. 50 It is approximately 5.6 μm.

[0039] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals contain D at room temperature. 50 It is approximately 5.7 μm.

[0040] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals contain D at room temperature. 50 It is approximately 5.8 μm.

[0041] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals contain D at room temperature. 50 It is approximately 5.9 μm.

[0042] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals contain D at room temperature. 50 It is approximately 6.0 μm.

[0043] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals contain D at room temperature. 50 It is approximately 6.1 μm.

[0044] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals contain D at room temperature. 50 It is approximately 6.2 μm.

[0045] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals contain D at room temperature. 50 It is approximately 6.3 μm.

[0046] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals contain D at room temperature. 50 It is approximately 6.4 μm.

[0047] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals contain D at room temperature. 50 It is approximately 6.5 μm.

[0048] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals contain D at room temperature. 50 It is approximately 6.6 μm.

[0049] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals contain D at room temperature. 50 It is approximately 6.7 μm.

[0050] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals contain D at room temperature. 50 It is approximately 6.8 μm.

[0051] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals contain D at room temperature. 50 It is approximately 6.9 μm.

[0052] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals contain D at room temperature. 50 It is approximately 7.0 μm.

[0053] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals contain D at room temperature. 50 It is approximately 7.1 μm.

[0054] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals contain D at room temperature. 50 It is approximately 7.2 μm.

[0055] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals contain D at room temperature. 50 It is approximately 7.3 μm.

[0056] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals contain D at room temperature. 50 It is approximately 7.4 μm.

[0057] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals contain D at room temperature. 50 It is approximately 7.5 μm.

[0058] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals contain D at room temperature. 50 It is approximately 7.6 μm.

[0059] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals contain D at room temperature. 50 It is approximately 7.7 μm.

[0060] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals contain D at room temperature. 50 It is approximately 7.8 μm.

[0061] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals contain D at room temperature. 50 It is approximately 7.9 μm.

[0062] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals contain D at room temperature. 50 It is approximately 8.0 μm.

[0063] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals contain D at room temperature. 50 It is approximately 8.1 μm.

[0064] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals contain D at room temperature. 50 It is approximately 8.2 μm.

[0065] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals contain D at room temperature. 50 It is approximately 8.3 μm.

[0066] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals contain D at room temperature. 50 It is approximately 8.4 μm.

[0067] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals contain D at room temperature. 50 It is approximately 8.5 μm.

[0068] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals contain D at room temperature. 50 It is approximately 8.6 μm.

[0069] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals contain D at room temperature. 50 It is approximately 8.7 μm.

[0070] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals contain D at room temperature. 50 It is approximately 8.8 μm.

[0071] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals contain D at room temperature. 50 It is approximately 8.9 μm.

[0072] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals contain D at room temperature. 50 It is approximately 9.0 μm.

[0073] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals contain D at room temperature. 50 It is approximately 9.1 μm.

[0074] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals contain D at room temperature. 50 It is approximately 9.2 μm.

[0075] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals contain D at room temperature. 50 It is approximately 9.3 μm.

[0076] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals contain D at room temperature. 50 It is approximately 9.4 μm.

[0077] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals contain D at room temperature. 50 It is approximately 9.5 μm.

[0078] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals contain D at room temperature. 50 It is approximately 9.6 μm.

[0079] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals contain D at room temperature. 50 It is approximately 9.7 μm.

[0080] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals contain D at room temperature. 50 It is approximately 9.8 μm.

[0081] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals contain D at room temperature. 50 It is approximately 9.9 μm.

[0082] Furthermore, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystals contain D at room temperature. 50 It is approximately 10.0 μm.

[0083] Another object of this disclosure is to provide a ropivacaine crystal having a specific crystal size distribution width (SPAN) value. In this disclosure, the size distribution width (SPAN) value is an indicator characterizing the crystal grain size distribution or crystal size distribution, calculated using the standard deviation and percentiles of the grain size distribution, as follows:

[0084] SPAN = (D 90 -D 10 ) / D 50

[0085] Among them, D 90 This refers to the particle size distribution where 90% of the particles are smaller than this value, i.e., the 90th percentile. (D) 10 This refers to the particle size distribution where 10% of the particles are smaller than this value, i.e., the 10th percentile. (D) 50 This refers to the particle size distribution in which 50% of the particles are smaller than this value, i.e., the median particle size.

[0086] In one technical solution of this disclosure, the crystal grain size distribution width (SPAN) value of the ropivacaine crystal is less than or equal to 2.

[0087] In one technical solution of this disclosure, the crystal grain size distribution width (SPAN) value of the ropivacaine crystal is about 1 to 2.

[0088] In one technical solution of this disclosure, the crystal grain size distribution width (SPAN) value of the ropivacaine crystal is about 1 to 1.9.

[0089] In one technical solution of this disclosure, the crystal grain size distribution width (SPAN) value of the ropivacaine crystal is about 1 to 1.8.

[0090] In one technical solution of this disclosure, the crystal grain size distribution width (SPAN) value of the ropivacaine crystal is about 1 to 1.7.

[0091] In one technical solution of this disclosure, the crystal grain size distribution width (SPAN) value of the ropivacaine crystal is about 1 to 1.6.

[0092] In one technical solution of this disclosure, the crystal grain size distribution width (SPAN) value of the ropivacaine crystal is about 1 to 1.5.

[0093] In one technical solution of this disclosure, the crystal grain size distribution width (SPAN) value of the ropivacaine crystal is about 1 to 1.4.

[0094] In one technical solution of this disclosure, the crystal grain size distribution width (SPAN) value of the ropivacaine crystal is about 1 to 1.3.

[0095] In one technical solution of this disclosure, the crystal grain size distribution width (SPAN) value of the ropivacaine crystal is about 1 to 1.2.

[0096] In one technical solution of this disclosure, the crystal grain size distribution width (SPAN) value of the ropivacaine crystal is about 1 to 1.1.

[0097] In one embodiment of this disclosure, the crystal grain size distribution width (SPAN) value of the ropivacaine crystal is approximately 1.

[0098] In one technical solution of this disclosure, the crystal grain size distribution width (SPAN) value of the ropivacaine crystal is approximately 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0.

[0099] Another object of this disclosure is to provide a ropivacaine crystal having the following properties: Figure 1 The XRPD diffraction pattern shown.

[0100] In one technical solution of this disclosure, the X-ray powder diffraction pattern of the ropivacaine crystal includes one or more of the following characteristic peaks: 8.894, 10.485, 13.045, 13.580, 14.300, 16.348, 17.918, 19.122, 19.470, 19.984, 20.315, 21.107, 22.567, 23.529, 24.459, 25.593, 26.309, 31.295, 31.880, 32.449.

[0101] In one technical solution of this disclosure, the ropivacaine crystal of this disclosure has Figure 5 The particle morphology is shown.

[0102] Furthermore, in the ropivacaine crystals disclosed herein, at least about 80% of the crystals possess... Figure 5 The particle morphology is shown.

[0103] Furthermore, in the ropivacaine crystals disclosed herein, at least about 85% of the crystals possess... Figure 5 The particle morphology is shown.

[0104] Furthermore, in the ropivacaine crystals disclosed herein, at least about 90% of the crystals possess... Figure 5 The particle morphology is shown.

[0105] Furthermore, in the ropivacaine crystals disclosed herein, at least about 95% of the crystals possess... Figure 5 The particle morphology is shown.

[0106] The ropivacaine crystals disclosed herein can be prepared by non-physical methods. These non-physical methods include shearing, cutting, grinding, and stamping.

[0107] Another object of this disclosure is to provide a method for preparing ropivacaine crystals, comprising:

[0108] Dissolve ropivacaine hydrochloride in a solvent and stir until completely dissolved;

[0109] After complete dissolution, adjust the pH of the solution to alkaline to induce crystallization.

[0110] Heat the solution and keep it warm.

[0111] This groundbreaking discovery reveals that, without altering the crystal lattice, different solvents can be used to crystallize ropivacaine crystals with varying crystal habits.

[0112] In one technical solution disclosed herein, the solvent is water.

[0113] In one of the technical solutions disclosed herein, when ropivacaine hydrochloride is dissolved in water, no other auxiliary reagents, such as dispersants, need to be added.

[0114] In one technical solution disclosed herein, the aspect ratio of the obtained ropivacaine crystal is 1:(1-2), at which point D 50 With a particle size of 5-10 μm and a particle size distribution width (SPAN) value of less than 2, it has the smallest specific surface area, stable structure, the slowest release rate in dissolution tests, the strongest sustained-release ability, and better clinical advantages.

[0115] In one of the technical solutions disclosed herein, the crystallization temperature is less than 40°C.

[0116] In one of the technical solutions disclosed herein, the crystallization temperature is room temperature or ambient temperature.

[0117] In one technical solution of this disclosure, adjusting the pH of the solution to alkaline means adjusting the pH value to approximately greater than 7, for example: pH 7.5, pH 8.0, pH 8.5, pH 9.0, pH 9.5, pH 10.0, pH 10.5, pH 11.0, pH 11.5, pH 12.0. Acids, bases, buffer solutions, etc., known in the art can be used to adjust the pH value of the solution. Commonly used acids and bases include hydrochloric acid, sulfuric acid, organic acids, sodium hydroxide, potassium hydroxide, phosphate buffer solutions, etc. The method for adjusting the pH of the solution disclosed in this disclosure is not limited; other suitable acids or bases can also be used in the method of this disclosure.

[0118] Typically, the pH of the ropivacaine solution is adjusted to a range of 7 to 12, preferably 8 to 11, and more preferably 9 to 10.

[0119] The inventors discovered that the higher the heating temperature, the shorter the time required to achieve the same particle size. In one technical solution disclosed herein, the heating temperature of the solution is 80–100°C, for example: 80°C, 81°C, 82°C, 83°C, 84°C, 85°C, 86°C, 87°C, 88°C, 89°C, 90°C, 81°C, 92°C, 93°C, 94°C, 95°C, 96°C, 97°C, 98°C, 99°C, and 100°C.

[0120] The inventors discovered that the particle size of ropivacaine crystals increases with prolonged holding time. In one technical solution of this disclosure, when the heating temperature is ≥90℃, the holding time is not less than 10 minutes. Preferred holding times are 10-100 minutes, for example: not less than 15 minutes, not less than 20 minutes, not less than 25 minutes, not less than 30 minutes, not less than 35 minutes, not less than 40 minutes, not less than 45 minutes, not less than 50 minutes, not less than 55 minutes, not less than 60 minutes, not less than 65 minutes, not less than 70 minutes, not less than 75 minutes, not less than 80 minutes, not less than 85 minutes, not less than 90 minutes, not less than 95 minutes, or not less than 100 minutes.

[0121] In one technical solution of this disclosure, when 80℃≤heating temperature<90℃, the heat preservation time is not less than 1 hour, and the preferred heat preservation time is 1 hour to 5 hours, for example: heat preservation time is not less than 1.5 hours, not less than 2 hours, not less than 2.5 hours, not less than 3 hours, not less than 3.5 hours, not less than 4 hours, not less than 4.5 hours, and not less than 5 hours.

[0122] Another object of this disclosure is to provide a pharmaceutical composition comprising the aforementioned ropivacaine crystals. In one embodiment of this disclosure, the pharmaceutical composition may be in various forms, such as a solid dosage form, a liquid composition, an emulsion, a suspension, a powder for injection, or a dry preparation. The pharmaceutical composition optionally includes at least one other pharmaceutically acceptable ingredient selected from the following, depending on the method of administration and dosage form: carriers, diluents, adjuvants, excipients, preservatives, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants, dispersants, thermosensitive materials, temperature regulators, adhesives, stabilizers, suspending agents, etc. The pharmaceutical composition can be prepared using methods known in the art.

[0123] Another object of this disclosure is to provide a method for treating or preventing postoperative pain, comprising administering the aforementioned pharmaceutical composition containing ropivacaine crystals to an individual in need. The pharmaceutical composition of this disclosure can be administered to an individual in need via local or systemic administration. Specifically, it can be administered orally, by injection, transdermally, or in dosage units comprising a conventional, non-toxic, pharmaceutically acceptable carrier.

[0124] The pharmaceutical products or pharmaceutical compositions disclosed herein can be delivered parenterally, i.e., administered intravenously (IV), intraventricularly (ICV), subcutaneously (SC), intraperitoneally (IP), intramuscularly (IM), subcutaneously (SD), or intradermally (ID), by direct injection, such as rapid concentration or continuous infusion. Formulations for injection may be presented in unit dosage forms, such as in ampoules or multi-dose containers with added preservatives. The compositions may be in the form of excipients, suspensions, solutions, or emulsions in oil or aqueous carriers, and may contain formulation agents such as anti-settling agents, stabilizers, and / or dispersants. Alternatively, the active ingredient may be reconstituted in powder form with a suitable carrier (e.g., sterile, pyrogen-free water) prior to use.

[0125] This disclosure optimizes the preparation process of ropivacaine crystals, particularly by selecting the solvent used in the crystallization process and by heating and holding the crystals at a specific temperature, resulting in ropivacaine crystals with specific morphologies, including but not limited to specific aspect ratios, specific particle size distribution widths, and specific particle size ranges. The inventors have discovered that by selecting different crystallization solvents without altering the crystal lattice, the resulting ropivacaine crystals exhibit the smallest specific surface area, the most stable structure, good reconstitution properties when formulated into lyophilized preparations, the slowest release rate in dissolution tests, and the strongest sustained-release capacity, thus offering greater clinical advantages. Attached Figure Description

[0126] Figure 1 XRPD pattern of ropivacaine crystals prepared in Example 1.

[0127] Figure 2 Morphology of ropivacaine crystals prepared in Comparative Example 1

[0128] Figure 3 Morphology of ropivacaine crystals prepared in Comparative Example 2

[0129] Figure 4 Morphology of ropivacaine crystals prepared in Comparative Example 3

[0130] Figure 5 Morphology of the ropivacaine crystals prepared in Example 1

[0131] Figure 6A Crystalline image of crystal formation after 0 minutes of heat preservation at 90℃.

[0132] Figure 6B Crystalline image of crystal formation after 30 minutes of heat preservation at 90℃.

[0133] Figure 6C Crystalline image of crystal formation after 60 minutes of heat preservation at 90℃.

[0134] Figure 6D Crystalline image of crystal formation after being kept at 90℃ for 90 minutes.

[0135] Figure 7 Particle size distribution under 90℃ insulation conditions (single crystal D) 50 Particle size growth trend with heat preservation time

[0136] Figure 8A Crystalline image of crystal formation after 0 hours of heat preservation at 80℃.

[0137] Figure 8B Crystalline image of crystal formation after being kept at 80℃ for 1 hour.

[0138] Figure 8D Crystalline image of crystal formation after being kept at 80℃ for 3 hours

[0139] Figure 8F Crystalline image of crystal formation after being kept at 80℃ for 4.5 hours.

[0140] Figure 9 Particle size distribution under 80℃ heat preservation conditions (single crystal D) 50 Particle size growth trend with heat preservation time

[0141] Figure 10A Morphology of ropivacaine crystals prepared at a crystallization temperature of 40℃

[0142] Figure 10B Morphology of ropivacaine crystals prepared at a crystallization temperature of 90℃

[0143] Figure 11 In vitro release curves of compositions 1-3 and 5

[0144] Figure 12 Plasma drug concentration-time curves after intramuscular injection of different samples in rats

[0145] Figure 13 Scanning electron microscope image of crystals formed by incubating ropivacaine solution at 80°C for 1 hour after crystallization.

[0146] Figure 14 Scanning electron microscope image of crystals formed by incubating ropivacaine solution at 90°C for 25 minutes after crystallization. Detailed Implementation

[0147] Based on the above content of this disclosure, and in accordance with common technical knowledge and practices in the field, various other modifications, substitutions, or alterations can be made without departing from the basic technical ideas of this disclosure.

[0148] I. Definition

[0149] Unless otherwise expressly stated, throughout the specification and claims, the term "comprising" or its variations such as "including" or "comprising" shall be understood to include the stated elements or components without excluding other elements or other components.

[0150] The term “optional” or “optionally” means that the event or situation described below may or may not occur, including both the occurrence and non-occurrence of the event or situation.

[0151] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that are suitable for use in human and animal tissues to the extent of reasonable medical judgment without excessive toxicity, irritation, allergic reactions, or other problems or complications in proportion to a reasonable benefit / risk ratio.

[0152] The term "treatment" includes the suppression, relief, prevention, or elimination of one or more symptoms or side effects associated with the disease, condition, or disorder being treated. The term "effective dose" or "therapeutic effective dose" refers to a dose sufficient to treat, suppress, or reduce one or more symptoms of the treated disease state or otherwise provide the desired pharmacological and / or physiological effect. Precise dosages will vary depending on a variety of factors, such as subject-dependent variables (e.g., age, immune system health, etc.), the disease or disorder, and the treatment administered. The effect of an effective dose can be relative to a control. These controls are known in the art and discussed herein, and can be, for example, the condition of the subject before or without administration of the drug or combination of drugs, or, in the case of a combination of drugs, the combined effect can be compared to the effect of administration of only one drug.

[0153] The term "pharmaceutical composition" means a composition comprising the compounds described in this disclosure or their pharmaceutically acceptable salts, and at least one pharmaceutically acceptable ingredient selected from the following, depending on the manner of administration and the nature of the dosage form: carriers, diluents, adjuvants, excipients, preservatives, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants, dispersants, thermosensitive materials, temperature regulators, adhesives, stabilizers, suspending agents, etc.

[0154] The term "about" indicates and covers a specified value as well as a range greater than and less than that value. In some embodiments, the term "about" may represent a variation of ±0.1%, ±0.2%, ±0.5%, ±1%, ±2%, ±3%, ±4%, ±5%, ±6%, ±7%, ±8%, ±9%, or ±10%. In some embodiments, where applicable, the term "about" represents a specified value ± one standard deviation of that value.

[0155] The endpoints and any values ​​of the ranges disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.

[0156] In this disclosure, the term "room temperature" refers to a temperature in the range of 20°C to 30°C.

[0157] In this disclosure, the definition of crystal habit is consistent with the definition commonly used in the art.

[0158] In this disclosure, the particle size specifically refers to the particle size detected after the suspension has undergone ultrasonic disruption and dispersion treatment (under a microscope, the suspended particles appear dispersed into individual crystals). If the suspension is not dispersed and the particle size is detected directly, the crystals will have varying degrees of aggregation, and the detected particle size cannot represent the true size of the crystals.

[0159] In this disclosure, the D 10 D 50 D 90 Both represent parameters indicating particle size; D 10 This refers to the particle size at which the cumulative particle size distribution number of a sample reaches 10%. Physically, it means that 10% of the particles are smaller than this value. 50 This refers to the particle size at which the cumulative particle size distribution percentage of a sample reaches 50%; its physical meaning is that particles larger than this value account for 50%, and particles smaller than this value also account for 50%. (D) 50 Also called median diameter or median grain size, it is often used to represent the average grain size of crystals; D 90 It refers to the particle size corresponding to 90% of the cumulative particle size distribution of a sample. Its physical meaning is that 90% of the particles are smaller than it.

[0160] In this disclosure, when used with respect to form, "substantially pure" means a compound having a purity of greater than 90 wt% based on the weight of the compound, including greater than 90, 91, 92, 93, 94, 95, 96, 97, 98, and 99 wt%, and also including a purity of approximately 100 wt% of a specific solid form of ropivacaine. The remaining material comprises one or more other forms of the compound, or reactive impurities, or processing impurities arising from its preparation. For example, a crystalline form of ropivacaine may be considered substantially pure because it has a purity of greater than 90 wt% as measured by means known and generally accepted in the art at this time, wherein the remaining less than 10 wt% of the material comprises one or more other forms of ropivacaine, reactive impurities, or processing impurities.

[0161] In this disclosure, the term "pharmaceuticalally acceptable excipient" refers to a substance that does not exhibit significant pharmacological activity at a given dose and is added to a pharmaceutical composition in addition to the active pharmaceutical ingredient. Excipients can function as mediators, diluents, releasing agents, disintegrants, dissolution modifiers, absorption enhancers, stabilizers, or manufacturing aids. Excipients may include fillers (diluents), binders, disintegrants, lubricants, and flow aids.

[0162] In this disclosure, the terms "filler" or "diluent" refer to substances used to dilute the active pharmaceutical ingredient prior to delivery. Diluents and fillers may also be used as stabilizers.

[0163] In this disclosure, the term "binder" refers to a substance that binds an active pharmaceutical ingredient and a pharmaceutically acceptable excipient together to maintain aggregated and dispersed portions.

[0164] In this disclosure, the term "disintegrant or disintegrating agent" refers to a substance, when added to a solid pharmaceutical composition, that promotes the breakdown or disintegration of the active pharmaceutical ingredient after administration and allows it to be released as efficiently as possible so that it dissolves rapidly.

[0165] In this disclosure, the term "lubricant" refers to a substance added to a powder blend to prevent compacted powder lumps from adhering to equipment during tableting or encapsulation. They facilitate tablet ejection from the mold and can improve powder flowability.

[0166] In this disclosure, the term "flow aid" refers to a substance used in tablet and capsule formulations to improve flow properties during tablet compression and to produce an anti-caking effect.

[0167] II. Examples

[0168] The present disclosure is further illustrated below with reference to embodiments. The description of specific exemplary embodiments of the present disclosure is for illustrative and explanatory purposes. These descriptions are not intended to limit the present disclosure to the precise forms disclosed, and it will be apparent that many changes and variations can be made in accordance with the teachings of this specification. The exemplary embodiments were chosen and described in order to explain the specific principles of the present disclosure and their practical application, thereby enabling those skilled in the art to implement and utilize various different exemplary embodiments of the present disclosure, as well as various different choices and variations.

[0169] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0170] Unless otherwise specified, all materials and reagents used in the following examples are commercially available.

[0171] Materials and methods

[0172] Ropivacaine crystals prepared in the following examples and comparative examples were analyzed using a Malvern static particle size, shape and chemical composition analyzer (model MOR2810, manufacturer: Malvern Panaco) and X-ray powder diffraction.

[0173] Sample processing:

[0174] Mix 2 ml of the drug solution with 6 ml of 0.1% Tween 80 in a vial, mix well, disperse using a Sonics VCX150 ultrasonic disruptor, and then add the dispersed optical concentration dropwise to a range of 5%–10% for measurement. The ultrasonic disruption parameters are as follows: power 37.5 W, 10 seconds of ultrasonication followed by a 5-second pause, for a total ultrasonic duration of 10 minutes.

[0175] Other testing methods and conditions were determined in accordance with known general methods in the field and did not exceed the scope of the prior art in the field.

[0176] Comparative Example 1

[0177] Weigh an appropriate amount of ropivacaine and add 10 times its weight of ethanol solution. Heat at 55°C to dissolve. After complete dissolution, allow the solution to crystallize at room temperature. Separate the resulting crystals from the solution. Disperse the separated crystals using ultrasonication according to the sample processing procedure, and then observe them under a microscope. Results: Microscopic observation revealed that the aspect ratio of the crystals was 1:(4~10), D 50 =18.6μm, SPAN=3.1, see Figure 2 .

[0178] Comparative Example 2

[0179] Weigh an appropriate amount of ropivacaine and add 10 times its weight of isopropanol solution. Heat at 55°C to dissolve. After complete dissolution, allow the solution to crystallize at room temperature. Separate the resulting crystals from the solution. Disperse the separated crystals using ultrasonication according to the sample preparation procedure, and then observe them under a microscope. Results: Microscopic observation revealed that the aspect ratio of the ropivacaine crystals obtained under these preparation conditions was >1:10. 50 =36.4μm, SPAN=5.3, see Figure 3 .

[0180] Comparative Example 3

[0181] Weigh an appropriate amount of ropivacaine and an equal weight of mannitol, the lyophilization protectant, into a beaker. Add 80% tert-butanol aqueous solution, heat appropriately until dissolved by stirring, and dispense 6 ml into vials for lyophilization. Lyophilization parameters are shown in Table 1. Details of the obtained crystal formation are provided in [Table 1]. Figure 4 It is an irregular sheet with large differences in grain size and crystal size, and the length-to-width ratio is difficult to calculate. SPAN = 2.8.

[0182] Table 1: Freeze-drying parameters

[0183] freeze-drying stage Set temperature Heating (cooling) time Duration Set vacuum level freeze -45℃ 120min 120min N / A First drying stage 1 -30℃ 30min 300min 0.3mbar First drying stage 2 0℃ 30min 600min 0.3mbar Secondary drying stage 1 35℃ 60min 360min 0.02mbar

[0184] Example 1

[0185] Weigh an appropriate amount of ropivacaine hydrochloride, add water, and stir to dissolve at room temperature. After complete dissolution, add sodium hydroxide solution to adjust the pH to >9, and then separate the resulting crystals from the solution. The separated crystals were ultrasonically dispersed according to the sample processing procedure and then observed under a microscope. Results: The crystal particles obtained by this method appeared as regular cubic blocks, as shown in the figure. Figure 5 The aspect ratio is 1:(1-2), D 50 The particle size is 2.55 μm, and the SPAN is 1.6.

[0186] The X-ray powder diffraction pattern of the ropivacaine crystals prepared in Example 1 was determined using X-ray powder diffraction. The results are shown in [Figure number missing]. Figure 1 XRPD Figure 1 The ropivacaine hydrochloride crystals disclosed herein exhibit the following characteristic peaks: 8.894, 10.485, 13.045, 13.580, 14.300, 16.348, 17.918, 19.122, 19.470, 19.984, 20.315, 21.107, 22.567, 23.529, 24.459, 25.593, 26.309, 31.295, 31.880, and 32.449.

[0187] Example 2

[0188] This embodiment studies the effects of heat preservation temperature and time on crystal grain size.

[0189] Weigh an appropriate amount of ropivacaine hydrochloride, add water, and stir to dissolve at room temperature. After complete dissolution, add sodium hydroxide solution to adjust the pH to >9. Then heat the solution to 90℃-100℃, and shear disperse while heating. Take samples at different holding times to detect changes in single crystal size and crystal growth during the heating process.

[0190] Table 2 shows the trend of crystal grain size change over time under a 90℃ holding condition. As can be seen from Table 2, under a 90℃ holding condition, as the holding time increases, the single crystal grain size increases, the number of small-sized crystals decreases, the crystal size tends to be uniform, and the crystal grain size distribution width (SPAN) value eventually decreases to 1.1-1.3 during the holding period, while the aspect ratio of the crystal remains at 1-2.

[0191] Table 2: Trend of crystal grain size change over time at 90℃

[0192]

[0193] Figures 6A-6D The crystallography of ropivacaine is shown immediately after the solution was heated to 90°C, and at time points of 30, 60, and 90 minutes. Figures 6A-6D The changes show that the single crystal size of ropivacaine increases, while the crystal pits do not change significantly. The crystal pits and sizes tend to be consistent, and the aspect ratio of the crystals remains 1 to 2.

[0194] Figure 7 The crystal size D of ropivacaine was shown under a heat treatment condition of 90℃. 50 The trend of change with holding time. As can be seen from the figure, the single crystal grain size increases with the extension of holding time.

[0195] If the holding temperature is reduced to 80℃, the crystal growth rate decreases, and the trend of crystal grain size change over time is shown in Table 3.

[0196] Table 3: Trend of crystal grain size change over time at 80℃

[0197]

[0198] Figure 8A , 8B Figures 8A, 8B, 8D, and 8F show the results of measuring ropivacaine crystal growth at different time points after the solution was heated to 80°C. From the changes in 8A, 8B, 8D, and 8F, it can be seen that as the holding time increases, the single crystal size of ropivacaine increases, the crystal growth points and sizes tend to be consistent, the crystal growth points do not change significantly, and the aspect ratio of the crystals remains 1–2.

[0199] Figure 9 The crystal size D of ropivacaine was shown under a heat treatment condition of 80℃. 50 The trend of change with holding time. As can be seen from the figure, with the extension of holding time, the single crystal grain size increases, and the growth trend is similar to... Figure 7 near.

[0200] Figure 13 and Figure 14 The images show scanning electron microscope (SEM) images of ropivacaine crystals after crystallization, obtained by incubating at 80°C for 1 hour and 90°C for 25 minutes, respectively. The images reveal similar crystal growth patterns and particle sizes after the incubation period. Therefore, the incubation process, by increasing the heating temperature and extending the incubation time, can control the growth of ropivacaine crystals to the target particle size without altering the crystal shape, resulting in a more uniform crystal distribution.

[0201] Comparative Example 4

[0202] This comparative study investigated the effect of crystallization temperature on crystal growth formation.

[0203] Weigh an appropriate amount of ropivacaine hydrochloride, add water, stir to dissolve at 40°C, add sodium hydroxide solution to adjust pH > 9, and separate the resulting crystals from the solution. Disperse the separated crystals ultrasonically according to the sample processing procedure, and then observe under a microscope. Figure 10A .

[0204] The experiment was repeated with the crystallization water temperature changed to 90℃, and the crystals were observed under a microscope. The results are shown below. Figure 10B .

[0205] according to Figures 10A-10B It can be seen that ropivacaine crystals at temperatures between 40℃ and 90℃ are both rod-shaped and block-shaped, indicating that direct crystallization at water temperatures above 40℃ cannot produce SPAN crystals with a length-to-width ratio of 1:(1-2) in the range of 1-2 with high purity.

[0206] Example 3

[0207] Ropivacaine or ropivacaine hydrochloride was purified using different methods to obtain recrystallized products, which were then further prepared into ropivacaine suspensions with a particle size of 8–10 μm. The effect of crystallization on the properties of the formulation was investigated. The preparation methods are as follows:

[0208] 1. The ropivacaine crystals prepared in Comparative Examples 1-3, Example 1, and Example 2, which were heated at 90°C for 90 min, were filtered to remove the solvent and obtain relatively dry solids.

[0209] 2. Weigh 0.05g of polysorbate 80, 0.5g of sodium carboxymethyl cellulose and 2.0g of mannitol, add 80g of water to dissolve, and obtain the excipient solution.

[0210] 3. Mix the excipient solution from step 2 with 2g of purified ropivacaine, weigh to 100g, and shear and disperse under high-speed shearing with a Fluke shear head for 20min to ensure that the solid is completely and evenly dispersed.

[0211] 4. Control particle size variation: Homogenize the suspensions of Comparative Examples 1-3 and control the particle size to 8-10 μm.

[0212] 5. Dispense each suspension into vials, freeze-dry, and store.

[0213] 6. Determine the aspect ratio and D of ropivacaine in compositions 1-5 respectively. 10 D 50 D 90 The particle size distribution width (SPAN) value was tested using the same method as before, and the results are shown in Table 4.

[0214] The freeze-dried finished product was taken out and its particle size was measured after reconstitution. The results are shown in Table 4.

[0215] Table 4: Detection of Reconstitution State of Lyophilized Formulations

[0216]

[0217] As can be seen from Table 4, among the suspensions with D50 of 8-10 μm obtained by homogenization process in Comparative Examples 1-3 and the suspension obtained by directly mixing ropivacaine with excipients in Example 2, the suspension composition 5 prepared by ropivacaine crystals in Example 2 of this disclosure has the narrowest particle size distribution and the lowest SPAN value.

[0218] Example 4: Comparison of specific surface area of ​​ropivacaine

[0219] Using a recognized technique based on the Brunauer, Emmett, and Teller theories, the specific surface area of ​​ropivacaine with different crystals in Comparative Examples 1–3 and ropivacaine obtained by incubation at 90°C for 90 min in Example 2 was measured by the physical adsorption of nitrogen on the sample surface in each batch.

[0220] Inverse gas chromatography (IGC) was used to determine the surface energy of crystals. Approximately 300-600 mg of sample was loaded into a separate iGC silanized glass column and operated under a surface coating of a series of alkanes and polar probe molecules to determine the dispersion surface energy (SD) and acid-base adsorption free energy (ΔGSP). In this study, the sample column was pretreated with nitrogen carrier gas at 10 mL / min for 1 h at 30 °C and 0% relative humidity. Experiments were conducted at 30 °C with a total nitrogen flow rate of 10 mL / min, and dead volume correction was performed using methane.

[0221] The specific surface area of ​​all samples was determined by gas adsorption. The results are shown in Table 5 below.

[0222] Table 5: Specific surface area determined based on the octane adsorption isotherm used for peak maximum retention time

[0223]

[0224]

[0225] The results show that the ropivacaine crystals prepared in Example 2 have the smallest specific surface area and more uniform surface energy, thus exhibiting more stable flow behavior.

[0226] Example 5: Comparison of in vitro release experiments

[0227] The in vitro release rates of compositions 1-3 and composition 5 prepared in Example 3 were tested. The solutions were prepared to a concentration of 20 mg / ml using CZ1S dissolution medium (i.e., 0.05 M disodium hydrogen phosphate solution (pH 9.0)). A 1 ml syringe was used to draw the reconstituted drug solution, and the corresponding dissolution method was run. The paddle-type sample loading vessel was manually pushed to mix the drug solution (approximately 18 mg of ropivacaine) in the 1 ml syringe. After removing the needle, the syringe was placed perpendicular to the horizontal plane on the paddle-type sample loading port. All the drug solution was injected into the dissolution vessel. A threaded needle filter was then installed on the sampling port, and the solutions at each time point were filtered online.

[0228] Figure 11 The results showed that the release rate was Composition 2 > Composition 1 > Composition 3 > Composition 5. That is, the formulation containing ropivacaine crystals prepared according to this disclosure with specific morphology, specific aspect ratio and specific particle size distribution width (SPAN) value had the lowest release rate and the strongest sustained-release ability, which is of great clinical application value.

[0229] Example 6 In vivo study

[0230] This embodiment investigates the effect of crystal grain size on Pk.

[0231] The suspension of composition 1 was further homogenized once at a homogenization pressure of 1500 bar to obtain D. 50 =4.66μm, SPAN=1.52, suspension of composition 6; the suspension of composition 2 was further homogenized, homogenized 5 times to obtain D 50 =2.09μm, SPAN=1.36, composition 7 suspension.

[0232] Male SD rats were administered the drug via intramuscular injection at a dose of 31.5 mg / kg. Plasma samples were collected at different time points and analyzed by LC-MS / MS to investigate the pharmacokinetic characteristics of each formulation under the prescribed administration methods. The plasma concentration-time curves are shown in Figure 1, and the pharmacokinetic parameters are shown in Table 6. Figure 12 .

[0233] Table 6 Pharmacokinetic parameters of SD rats after intramuscular injection of CZ1S control group

[0234]

[0235] The results showed that by using mechanical means such as homogenization and milling to granulate ropivacaine crystals with different crystal sizes into a more regular shape with a crystal SPAN value ≤ 1.5, although the crystal SPAN value could be reduced, the crystal particle size would also decrease, resulting in poor sustained-release ability of the formulation.

[0236] Example 7: Comparison of pharmacokinetics of different crystal pituitary glands

[0237] This study investigated the dynamic changes in SD rats after a single subcutaneous or sciatic plexus injection of Composition 1, Composition 2, Composition 3, and Composition 5, and obtained relevant pharmacokinetic parameters.

[0238] Methods: Twenty-four male SD rats were randomly divided into eight groups (n=3 per group): a subcutaneous injection group (120 mg / kg) and a sciatic plexus injection group (80 mg / kg). Both groups received a single dose of 2 mL / kg. Blood samples were collected from each group before administration and at 0.5, 1, 2, 4, 8, 12, 24, 48, and 72 hours after administration. The concentration of ropivacaine in each plasma sample was determined by LC-MS / MS. Relevant pharmacokinetic parameters are detailed in Tables 7 and 8.

[0239] Table 7. Main pharmacokinetic parameters of ropivacaine in plasma of SD rats after a single subcutaneous injection.

[0240]

[0241] Table 8. Main pharmacokinetic parameters of ropivacaine in plasma of SD rats after a single sciatic plexus injection.

[0242]

[0243] The results show that the crystal suspension injection disclosed herein has superior pharmacokinetics in vivo: Compositions 2 and 3 have shorter half-lives and shorter times to peak concentration, possibly due to the higher proportion of smaller crystals in the composition, resulting in a faster release rate; Composition 5 has a longer half-life, indicating that the crystal protected by this patent can achieve sustained release.

Claims

1. Ropivacaine crystals, characterized in that, The aspect ratio of the ropivacaine crystal is approximately 1:(1-2).

2. The ropivacaine crystal of claim 1, wherein, The aspect ratio of the ropivacaine crystal is approximately 1:(1-1.9), or 1:(1-1.8), or 1:(1-1.7), or 1:(1-1.6), or 1:(1-1.5), or 1:(1-1.4), or 1:(1-1.3), or 1:(1-1.2), or 1:(1-1.1), or 1:

1.

3. The ropivacaine crystal of claim 1 or 2, wherein, The ropivacaine crystals comprise at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the crystals with an aspect ratio of about 1:(1 to 2).

4. The ropivacaine crystal according to any one of claims 1 to 3, wherein the ropivacaine crystal has a D at room temperature 50 It is approximately 5-10 μm.

5. The ropivacaine crystal according to claim 4, wherein the ropivacaine crystal has a D at room temperature 50 Approximately 5.0μm, 5.1μm, 5.2μm, 5.3μm, 5.4μm, 5.5μm, 5.6μm, 5.7μm, 5.8μm, 5.9μm, 6.0μm, 6.1μm, 6.2 μm, 6.3μm, 6.4μm, 6.5μm, 6.6μm, 6.7μm, 6.8μm, 6.9μm, 7.0μm, 7.1μm, 7.2μm, 7.3μm, 7.4μm, 7.5 μm, 7.6μm, 7.7μm, 7.8μm, 7.9μm, 8.0μm, 8.1μm, 8.2μm, 8.3μm, 8.4μm, 8.5μm, 8.6μm, 8.7μm, 8. 8μm, 8.9μm, 9.0μm, 9.1μm, 9.2μm, 9.3μm, 9.4μm, 9.5μm, 9.6μm, 9.7μm, 9.8μm, 9.9μm, or 10.0μm.

6. The ropivacaine crystals according to any one of claims 1 to 5, wherein at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the crystals at room temperature have a D... 50 It is approximately 5-10 μm.

7. Ropivacaine crystals characterized in that, The crystal size distribution width (SPAN) value of the ropivacaine crystal is less than or equal to 2.

8. The ropivacaine crystal according to claim 7, wherein the crystal grain size distribution width (SPAN) value of the ropivacaine crystal is about 1 to 2.

9. The ropivacaine crystal according to claim 7 or 8, wherein the crystal grain size distribution width (SPAN) value of the ropivacaine crystal is about 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.

0.

10. A ropivacaine crystal, characterized in that, The aspect ratio of the ropivacaine crystal is approximately 1:(1-2), and the crystal size distribution width (SPAN) value is less than or equal to 2.

11. Ropivacaine crystals characterized in that, The ropivacaine crystals described herein have the granular morphology shown in Figure 5.

12. The ropivacaine crystals of claim 1, wherein, The ropivacaine crystal has the XRPD diffraction pattern shown in Figure 1.

13. A method for preparing ropivacaine crystals, comprising: Dissolve ropivacaine hydrochloride in a solvent and stir until dissolved; After complete dissolution, adjust the pH to alkaline to induce crystallization. Heat the solution and keep it warm; The solvent is water.

14. The method of claim 13, wherein, The crystallization temperature is less than 40℃.

15. The method of claim 13 or 14, wherein, The crystallization temperature was room temperature.

16. The method of any one of claims 13-15, wherein, Adjust the pH value to be greater than 7, preferably greater than 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, or 12.

0.

17. The method of any one of claims 13-16, wherein, Heat the solution to 80–100°C.

18. The method of any one of claims 13-17, wherein, When the insulation temperature is ≥90℃, the insulation time shall not be less than 10 minutes; preferably, the insulation time shall not be less than 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 60 minutes, 65 minutes, 70 minutes, 75 minutes, 80 minutes, 85 minutes, 90 minutes, 95 minutes, or 100 minutes. When the insulation temperature is ≤80℃ and <90℃, the insulation time shall not be less than 1 hour; preferably, the insulation time shall not be less than 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, or 5 hours.

19. A pharmaceutical composition comprising ropivacaine crystals as described in any one of claims 1-12, or ropivacaine crystals prepared by the method according to any one of claims 13-18.

20. Use of the ropivacaine crystals of claims 1-12 or the pharmaceutical composition of claim 19 for the manufacture of a medicament for the prevention or treatment of postoperative pain.

Images