Novel crystal form of piperacillin acid as well as preparation method and application of novel crystal form

Abstract

The invention provides a novel crystal form of piperacillin acid, which is named as a crystal form A. The X-ray powder diffraction of the crystal form has characteristic diffraction peaks at 2theta angles of 5.6 + / -0.2 degrees, 10.2 + / -0.2 degrees, 12.8 + / -0.2 degrees, 16.4 + / -0.2 degrees, 18.7 + / -0.2 degrees, 20.5 + / -0.2 degrees, 22.3 + / -0.2 degrees, 24.1 + / -0.2 degrees, 25.8 + / -0.2 degrees and 27.5 + / -0.2 degrees, and in an infrared spectrum, the absorption peak intensity at 1760 cm <-1 > is enhanced by 15% compared with that of a traditional crystal form, and the absorption peak intensity at 1760 cm <-1 > is enhanced by 15% compared with that of a traditional crystal form. The crystallization environment of the beta-lactam ring is more ordered. The crystal form has excellent stability and bioavailability, especially shows remarkable advantages in an acid environment, overcomes the defects of a piperacillin acid crystal form in the prior art, and provides a material basis for developing higher-quality antibacterial drugs. In addition, the invention provides a preparation method, application and the like of the novel crystal form.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to a novel crystal form of piperacillinic acid, its preparation method, and its application in antibacterial drugs. Background Technology

[0002] Piperacillin is a broad-spectrum semi-synthetic penicillin antibiotic that exerts its antibacterial effect by inhibiting bacterial cell wall synthesis and is commonly used to treat Gram-negative bacterial infections. However, the existing crystalline forms of piperacillin suffer from poor stability and low bioavailability, affecting its clinical efficacy and formulation development. For example, the traditional crystalline form is easily degraded under acidic conditions, limiting the application of oral formulations. Summary of the Invention

[0003] This invention not only overcomes the stability problems and low bioavailability issues of existing technologies, but also provides a novel crystalline form of piperacillinic acid, named crystalline form A. Its X-ray powder diffraction exhibits characteristic diffraction peaks at 2θ angles of 5.6±0.2°, 10.2±0.2°, 12.8±0.2°, 16.4±0.2°, 18.7±0.2°, 20.5±0.2°, 22.3±0.2°, 24.1±0.2°, 25.8±0.2°, and 27.5±0.2°. Furthermore, in the infrared spectrum, at 1760 cm⁻¹... -1 The absorption peak intensity is 15% stronger than that of the traditional crystal form, indicating a more ordered crystallization environment of the β-lactam ring. This crystal form exhibits excellent stability and bioavailability, especially showing significant advantages in acidic environments, overcoming the defects of piperacillin acid crystal forms in existing technologies, and providing a material basis for the development of higher-quality antibacterial drugs.

[0004] A preparation method is also provided: the preparation method for crystal form A is simple and easy to implement, and readily applicable to industrial production. The specific steps are as follows:

[0005] Dissolution: Dissolve crude piperacillin acid in an ethanol-water mixed solvent (volume ratio 1:1) at a concentration of 50-100 mg / mL. This solvent system is conducive to the full dissolution of piperacillin acid and provides a suitable environment for subsequent crystal transformation and crystallization.

[0006] Crystallization: Add seed crystals at 0.1-1% of the crude product mass and stir at 25-30℃ for 12-24 hours to make the solution supersaturated and induce the formation of crystal form A. Then cool down to 0-5℃ and continue stirring for 6-12 hours. The temperature reduction further promotes the precipitation and growth of crystal form A, ensuring the quality and purity of the crystals.

[0007] Filtration and drying: The precipitated crystals were filtered and washed with cold ethanol to remove surface impurities and residual solvents. Finally, they were dried under vacuum drying conditions (40℃, 10mmHg) for 12 hours to obtain a white crystalline powder with a yield of about 85%. The obtained crystal form A has high purity and good stability, meeting the requirements for pharmaceutical use.

[0008] Pharmaceutical Composition: This invention also provides a pharmaceutical composition comprising the above-mentioned crystal form A and pharmaceutically acceptable excipients. The excipients are diverse and can be selected and combined according to specific dosage form requirements and routes of administration. For example, fillers such as microcrystalline cellulose, starch, and their derivatives can be used to provide sufficient volume and weight for the drug, facilitating formulation formation; disintegrants such as croscarmellose sodium, croscarmellose, and carboxymethyl starch sodium can rapidly disintegrate the drug in vivo, releasing the active ingredient and improving the drug's bioavailability; lubricants such as magnesium stearate, talc, and polyethylene glycol can improve the fluidity of the formulation, prevent particles from adhering to equipment or molds, and ensure the smooth progress of the formulation production process; coating materials such as hydroxypropyl methylcellulose phthalate, ethyl cellulose, and polyvinyl alcohol can be used to prepare enteric coatings or other special coatings to protect the stability of the drug in the acidic environment of the stomach, allowing the drug to be released at specific sites in the intestine, improving the drug's efficacy and safety.

[0009] application:

[0010] Antibacterial activity: Crystal form A exhibits significant antibacterial effects against Gram-negative bacteria such as Pseudomonas aeruginosa and Escherichia coli. Its minimum inhibitory concentration (MIC) is more than 50% lower than that of the traditional crystal form. This means that in clinical applications, antibacterial drugs prepared using crystal form A can effectively inhibit bacterial growth and reproduction at lower doses, reducing the amount of drug used and lowering the risk of adverse reactions in patients. It also helps to delay the development and progression of bacterial resistance, providing a more powerful weapon for anti-infective therapy.

[0011] Stability: In an acidic solution at pH 1.2, the degradation rate of crystal form A is less than 5% within 2 hours, while the degradation rate of conventional crystal forms exceeds 30%. This superior acid stability makes crystal form A ideal for developing oral formulations, as oral drugs pass through an acidic environment in the stomach. Higher acid stability ensures that the drug is not significantly degraded in the stomach, allowing it to reach the intestines smoothly and be effectively absorbed, thereby improving oral bioavailability and ensuring the drug's efficacy in vivo.

[0012] Bioavailability: The oral bioavailability of crystal form A reaches 65%, significantly higher than the 30% of the traditional crystal form. This means that crystal form A is absorbed faster and to a greater extent in the body, achieving an effective blood concentration more quickly to exert its antibacterial effect, shortening the treatment cycle for patients, and improving the cure rate. It also facilitates the development of special dosage forms such as sustained-release and controlled-release drugs, further optimizing the therapeutic effect of the drug.

[0013] Advantages in Formulation Development: Based on the unique advantages of crystal form A, various drug dosage forms can be developed, such as oral tablets, capsules, injections, and granules, to meet different clinical needs and patients' medication habits. Especially in oral formulations, combined with its excellent acid stability and high bioavailability, through rational selection of excipients and formulation process design, oral formulations with good taste, easy swallowing, excellent stability, and definite efficacy can be prepared, improving patient medication adherence and providing a wider range of choices and a better treatment experience for the clinical application of antibacterial drugs. Detailed Implementation

[0014] Example 1: Preparation of crystal form A

[0015] 1. Preparation of raw materials and reagents

[0016] Piperacillin acid crude product: Weigh 10g, ensuring that its purity meets the requirements for pharmaceutical raw materials and that the impurity content is controlled within the specified range, so as to ensure the smooth progress of the subsequent preparation process and the quality of the final crystal form.

[0017] Ethanol-water mixed solvent: Accurately measure 100 mL each of ethanol and water, and mix them evenly at a volume ratio of 1:1. This solvent system has been rigorously screened and verified, and can fully dissolve crude piperacillin acid. At the same time, it provides a suitable solvent environment for the formation of crystal form A, which is conducive to the transformation and growth of crystal form.

[0018] Seed crystal: Accurately weigh 0.05g of high-purity crystal form A seed crystal. The quality of the seed crystal is crucial to the formation of the induced crystal form. Its purity should reach 99% or higher, and the crystal structure should be complete and free of impurities.

[0019] 2. Dissolution process

[0020] Slowly add 10g of crude piperacillin to 200mL of ethanol-water mixture, turn on the stirrer and set the stirring speed to 300-400r / min to ensure that the crude product is fully dispersed in the solvent.

[0021] Under constant temperature water bath conditions of 25℃±2℃, stir continuously for 30 minutes to gradually dissolve the crude piperacillin acid and form a homogeneous solution. During this process, closely observe the appearance of the solution to ensure that there are no obvious particulate residues. If incomplete dissolution is found, the stirring time can be appropriately extended or the stirring speed can be slightly increased until complete dissolution.

[0022] 3. Crystallization process

[0023] To the completely dissolved solution, slowly add 0.05g of seed crystals, maintaining a constant temperature of 25℃±2℃ and a stirring speed of 300-400 rpm for 24 hours. This step aims to induce the piperacillin acid molecules in the solution to arrange themselves in an orderly manner according to the specific lattice structure of crystal form A through the induction of the seed crystals, forming tiny crystal nuclei that gradually grow. After stirring for 24 hours, slowly cool the solution to 0℃±2℃, controlling the cooling rate at 5-10℃ per hour to avoid excessively rapid cooling that could cause stress within the crystals or affect the crystal growth morphology. Continue stirring at 0℃ for 12 hours to promote further precipitation and growth of crystal form A, ensuring the integrity and purity of the crystals.

[0024] 4. Filtration and drying

[0025] The mixture after crystallization is filtered using a 0.45 μm pore size filter membrane, and the filter cake is collected. During filtration, care must be taken to control the filtration rate to avoid crushing the crystals or leaving crystals in the filtrate due to excessive filtration speed.

[0026] The filter cake is washed with ethanol pre-cooled to 0-5℃ 2-3 times, with 50mL used each time, to remove residual solvent, unreacted impurities and other impurities from the crystal surface and improve the purity of the crystal.

[0027] The washed filter cake was placed in a vacuum drying oven and dried for 12 hours at 40℃±2℃ and 10mmHg. During the drying process, the state of the crystals was observed regularly to ensure that the crystals did not agglomerate or deteriorate. Finally, 8.5g of white crystalline powder was obtained, with a yield of 85%.

[0028] 5. Crystal form identification X-ray powder diffraction (XRPD) analysis: A small amount of the prepared crystal form A sample was tested using a Bruker D8 Advance X-ray diffractometer under Cu-Kα ray conditions. The scanning range was 2θ = 3°-40°, the scanning rate was 5° / min, and the step size was 0.02°. The test results showed that the sample exhibited characteristic diffraction peaks consistent with the standard diffraction peaks of crystal form A at 2θ angles of 5.6±0.2°, 10.2±0.2°, 12.8±0.2°, 16.4±0.2°, 18.7±0.2°, 20.5±0.2°, 22.3±0.2°, 24.1±0.2°, 25.8±0.2°, and 27.5±0.2°. These peaks were sharp and symmetrical, with no other impurity peaks, indicating that the prepared sample was pure crystal form A.

[0029] Infrared spectroscopy (IR) analysis: The samples were tested using a Nicoleti S50 Fourier transform infrared spectrometer. The samples were prepared using the KBr pellet method, and the scanning range was 4000-400 cm⁻¹. -1 4cm resolution -1 The test results showed that the sample was at 3420cm. -1 (OH stretching vibration), 1760cm -1 (β-lactam ring C=O), 1680cm -1 (Carboxylic acid C=O), 1605cm -1 (Benzene ring skeleton vibration), 1510cm -1 (NH bending vibration), 1220cm -1 A characteristic absorption peak appears at (CO stretching vibration), and at 1760 cm⁻¹. -1 The absorption peak intensity is 15% stronger than that of the traditional crystal form, further confirming the structural characteristics and ordered crystal environment of crystal form A.

[0030] Example 2: Preparation of oral tablets

[0031] 1. Formulation and Selection of Raw Materials and Excipients

[0032] Crystal form A: 500mg, as the main drug component, exerts antibacterial and therapeutic effects. It has high bioavailability and excellent acid stability, which can ensure effective absorption and efficacy of the drug in the body.

[0033] Microcrystalline cellulose: 200mg, as a filler, pharmaceutical grade microcrystalline cellulose is selected, which has good flowability, compressibility and stability, and can increase the volume and weight of tablets, making it easier to form tablets and swallow them.

[0034] Cross-linked carboxymethyl cellulose sodium: 20mg. As a disintegrant, pharmaceutical-grade cross-linked carboxymethyl cellulose sodium is used, which has rapid disintegration properties, enabling the tablets to disintegrate rapidly in the body, releasing the main drug components and improving the bioavailability of the drug.

[0035] Magnesium stearate: 5mg, as a lubricant, pharmaceutical grade magnesium stearate is selected, which has good lubricity and anti-sticking properties, can improve the flowability of tablets, prevent particles from sticking to the die of the tablet press, and ensure smooth tablet compression and appearance quality.

[0036] 2. Preparation process

[0037] Mixing procedure: Place the weighed crystal form A, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate into a three-dimensional motion mixer. Set the mixing time to 15-20 minutes and the rotation speed to 10-15 r / min. During the mixing process, ensure that all components are thoroughly and evenly mixed to avoid uneven distribution of the active ingredient in the tablets, which could affect efficacy and quality.

[0038] Tableting Operation: Transfer the uniformly mixed granules to the tableting machine hopper. Set the tableting machine pressure to 10-15 kN, the tablet weight to 725 mg / tablet (corresponding to the above prescription dosage), and the tableting machine speed to 10-15 tablets / minute. During the tableting process, closely observe the appearance, hardness, and disintegration of the tablets to ensure that the tablets are intact, uniform in color, and of moderate hardness, meeting the quality requirements for pharmaceutical tablets.

[0039] Coating process: A fluidized bed coating machine is used to perform enteric coating on the compressed tablets. Hydroxypropyl methylcellulose phthalate (HPMCP) is selected as the coating material. The coating solution is prepared as follows: Accurately weigh a certain amount of HPMCP and add it to an appropriate amount of ethanol-water mixed solvent (volume ratio 7:3). Stir until the HPMCP is completely dissolved to form a homogeneous coating solution. The inlet air temperature is set at 40-50℃, and the inlet air volume is 0.5-0.8 m³ / h. 3 The spray rate is 0.1-0.2 MPa, and the coating weight gain is 10%-15%, ensuring that the tablet surface is uniformly coated with an enteric coating. This enteric coating can dissolve in the intestinal environment at pH 5.5-6.8, ensuring that the drug is not degraded in the acidic environment of the stomach, and smoothly reaches the intestine to release the drug, thereby improving the stability and bioavailability of the drug.

[0040] 3. Tablet quality evaluation

[0041] Appearance inspection: Visually inspect the tablets, ensuring a smooth surface, uniform color, no obvious spots, and no chipped edges or corners. Inspect 100 tablets, record the number of acceptable and unacceptable tablets, and calculate the appearance pass rate. The appearance pass rate must be no less than 98%.

[0042] Weight variation check: Randomly select 20 tablets, accurately weigh each tablet, and calculate the average tablet weight and the weight variation per tablet. According to the pharmacopoeia, the weight variation of tablets should be within ±7.5%. If more than 2 tablets exceed this range, the batch of tablets is deemed unqualified.

[0043] Hardness Testing: The tablets were tested using a tablet hardness tester. Ten tablets were randomly selected, and their hardness was tested individually. The average hardness was calculated. The average hardness of the tablets was required to be no less than 4 kg / cm². 2 This ensures that the tablets are not easily broken during packaging, transportation, and storage.

[0044] Disintegration time limit test: Following the disintegration time limit test method specified in the pharmacopoeia, the tablets were placed in simulated gastric fluid (pH 1.2), and the disintegration of the tablets was observed over 2 hours. The tablets were required not to disintegrate within 2 hours. Then, the tablets were transferred to simulated intestinal fluid (pH 6.8), and the disintegration of the tablets was observed. The tablets were required to completely disintegrate within 30 minutes. This test result verifies the quality of the enteric coating and the release performance of the tablets, ensuring that the drug is not released in the stomach but rapidly disintegrates and is absorbed in the intestines.

[0045] Relevant data:

[0046] I. Crystal form characterization data

[0047] 1. X-ray powder diffraction (XRPD)

[0048] Test conditions:

[0049] • Instrument: Bruker D8 Advance X-ray diffractometer

[0050] • Radiation source: Cu-Kα rays

[0051] • Scanning range: 2θ = 3° - 40°

[0052] • Scan rate: 5° / min

[0053] • Step size: 0.02°

[0054] • Sample preparation: Powder compression method

[0055] Characteristic diffraction peak data (Table 1):

[0056]

[0057] Conclusion: Crystal form A has unique and clear characteristic peaks, which are significantly different from the traditional crystal form (no characteristic peaks at 5.6° and 10.2°), proving that it is a new crystal form.

[0058] 2. Infrared Spectroscopy (IR)

[0059] Test conditions:

[0060] • Instrument: Nicoleti S50 Fourier Transform Infrared Spectrometer

[0061] Sample preparation: KBr tableting method

[0062] • Scanning range: 4000-400cm -1

[0063] • Resolution: 4cm -1

[0064] Characteristic absorption peak (cm) -1 Crystal form A exhibits vibrations at 3420 cm⁻¹ (OH stretching vibration), 1760 cm⁻¹ (β-lactam ring C=O), 1680 cm⁻¹ (carboxylic acid C=O), 1605 cm⁻¹ (benzene ring skeletal vibration), 1510 cm⁻¹ (NH bending vibration), and 1220 cm⁻¹ (CO stretching vibration). Compared to traditional crystal forms, crystal form A has a higher vibration at 1760 cm⁻¹. -1 The absorption peak intensity increased by 15%, indicating that the crystallization environment of the β-lactam ring is more ordered.

[0065] II. Stability Test Data

[0066] 1. Acid degradation stability (pH 1.2 simulated gastric juice)

[0067] Test method:

[0068] • Sample concentration: 1 mg / mL (Crystal form A vs. conventional crystal form)

[0069] Medium: 0.1M HCl (pH 1.2)

[0070] Temperature: 37±0.5℃

[0071] Sampling time: 0, 0.5, 1, 2 hours

[0072] • Detection method: HPLC (C18 column, mobile phase: acetonitrile-0.1% phosphoric acid aqueous solution (20:80), wavelength 225nm)

[0073] Comparison of degradation rates (Table 2)

[0074]

[0075] 2. Accelerated stability testing (ICH Q1A guideline)

[0076] Conditions: 40℃±2℃ / 75%RH±5%RH, stored for 6 months. Detection indicators: content (HPLC), related substances (maximum single impurity, total impurities).

[0077] Results (Table 3):

[0078]

[0079] III. Antibacterial Activity Data

[0080] 1. Determination of minimum inhibitory concentration (MIC)

[0081] Method: Broth dilution method (CLSIM07-A10 standard) for testing strains:

[0082] Gram-negative bacteria: *Pseudomonas aeruginosa* ATCC 27853, *Escherichia coli* ATCC 25922, *Klebsiella pneumoniae* ATCC 700603

[0083] Gram-positive bacteria: Staphylococcus aureus ATCC 29213 (control strain, piperacillin has weak activity against it).

[0084] MIC values ​​(μg / mL) (Table 4):

[0085]

[0086] 2. In vitro sterilization curve

[0087] Test strain: Pseudomonas aeruginosa ATCC 27853 (initial bacterial concentration 1×10⁻⁶) 6 CFU / mL) Drug concentration: 4×MIC (Crystal form A: 8 μg / mL; Conventional crystal form: 16 μg / mL) Sampling time: 0, 2, 4, 6, 8 hours

[0088] Changes in the logarithmic number of viable bacteria (log CFU / mL):

[0089] • Crystal form A: Viable bacteria count decreased from 6.0 to <3.0 within 8 hours (sterilization rate >99.9%)

[0090] • Traditional crystal form: viable bacteria count reduced to 4.5 after 8 hours (90% sterilization rate)

[0091] IV. Bioavailability Data (Oral Administration to SD Rats)

[0092] 1. Experimental Design

[0093] • Animals: Male SD rats (200±20g), n=6 / group

[0094] • Dosage: 50 mg / kg (calculated as piperacillinic acid)

[0095] Sampling time: 0, 0.25, 0.5, 1, 2, 4, 6, 8, 12 hours

[0096] • Detection method: LC-MS / MS (plasma sample preparation: protein precipitation method, C18 column, mobile phase acetonitrile-0.1% formic acid water (40:60), mass spectrometry multiple reaction monitoring (MRM) mode)

[0097] 2. Pharmacokinetic parameters (Table 5)

[0098]

[0099] Conclusion: The oral bioavailability of crystal form A is 2.17 times that of the conventional crystal form, with a shorter time to peak concentration and higher blood concentration, indicating that it is absorbed faster and more completely.

[0100] V. Data Validity Statement

[0101] Methodological validation:

[0102] • The precision RSD of HPLC detection of the content is <2%, and the recovery rate is 98%-102%;

[0103] The limit of quantification for piperacillin acid in plasma by LC-MS / MS is 0.1 μg / mL, with a matrix effect of <15%.

[0104] Repeatability:

[0105] • Crystal form preparation repeatability: The XRPD spectra of the three batches of samples were consistent, with a yield of 82%-87%;

[0106] • Stability test: The RSD of the three parallel sample groups was all <5%.

[0107] The above data proves that crystal form A is significantly superior to existing technologies in terms of structural novelty, stability, antibacterial activity and bioavailability, fully supporting the core innovations of "novel crystal form" and "performance optimization" in the patent claims.

[0108] Beneficial effects

[0109] • Improved stability: Crystal form A exhibits significantly enhanced stability in acidic environments, making it suitable for developing oral formulations.

[0110] • Optimized efficacy: Improved antibacterial activity and bioavailability can reduce the dosage and frequency of administration.

[0111] • Process advantages: The preparation method is simple and easy to industrialize.

[0112] Technological Innovation Points

[0113] 1. Novel crystal form: The crystal form A of piperacillin acid is disclosed for the first time, and its stability and bioavailability are significantly better than existing crystal forms.

[0114] 2. Preparation method: A stepwise crystallization process was adopted to achieve controllable preparation of high-purity crystal forms. 3. Formulation application: Based on the stability of crystal form A, an oral enteric-coated formulation was developed, expanding its clinical applications.

Claims

1. A crystal form A of piperacillin acid, characterized in that: X-ray powder diffraction exhibits characteristic diffraction peaks at 2θ angles of 5.6±0.2°, 10.2±0.2°, 12.8±0.2°, 16.4±0.2°, 18.7±0.2°, 20.5±0.2°, 22.3±0.2°, 24.1±0.2°, 25.8±0.2°, and 27.5±0.2°.

2. The crystalline form A of piperacillin acid according to claim 1, characterized in that the characteristic absorption peak of the infrared spectrum of crystalline form A is at 3420 cm⁻¹. -1 (OH stretching vibration), 1760cm -1 (β-lactam ring C=O), 1680cm -1 (Carboxylic acid C=O), 1605cm -1 (Benzene ring skeleton vibration), 1510cm -1 (NH bending vibration), 1220cm -1 It exhibits significant absorption characteristics at the (CO stretching vibration) site.

3. The method for preparing crystal form A according to claim 1, characterized in that: Dissolution: Dissolve crude piperacillin acid in an ethanol-water mixture (volume ratio 1:1) to a concentration of 50-100 mg / mL; Crystallization: Add seed crystals (0.1-1% of the crude material) and stir at 25-30℃ for 12-24 hours, then cool to 0-5℃ and continue stirring for 6-12 hours; Filtration and drying: The precipitated crystals were filtered, washed with cold ethanol, and vacuum dried (40℃, 10mmHg) for 12 hours to obtain a white crystalline powder.

4. A pharmaceutical composition, characterized in that: The product comprises crystal form A as described in claim 1 and pharmaceutically acceptable excipients, including but not limited to fillers, disintegrants, lubricants, and coating materials, wherein the filler is selected from microcrystalline cellulose, starch, and their derivatives; the disintegrant is selected from croscarmellose sodium, croscarmellose, and carboxymethyl starch sodium; the lubricant is selected from magnesium stearate, talc, and polyethylene glycol; and the coating material is selected from hydroxypropyl methylcellulose phthalate, ethyl cellulose, and polyvinyl alcohol.

5. The use of crystal form A according to claim 1 in the preparation of antibacterial drugs, characterized in that: The antibacterial drug is used to treat Gram-negative bacterial infections.

6. The use of crystal form A according to claim 5 in the preparation of antibacterial drugs, characterized in that: This antibacterial drug is effective against respiratory infections, urinary tract infections, and skin and soft tissue infections caused by Pseudomonas aeruginosa, Escherichia coli, and Klebsiella pneumoniae. It also exhibits a stability advantage, with crystal form A degrading at less than 5% within 2 hours in an acidic solution at pH 1.2, compared to over 30% for traditional crystal forms. Furthermore, animal studies have shown that crystal form A has an oral bioavailability of 65%, significantly higher than the 30% bioavailability of traditional crystal forms.

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