Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/02—Inorganic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
  • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
  • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

• the present invention relates to a stable lyophilized injectable formulation comprising Centhaquine or its water–soluble salts which can be administered via intravenous route and is suitable for therapeutic use in managing hypovolemic shock.
• Centhaquine citrate is a white crystalline powder with empirical formula C28H33N3O7 and a molecular weight of 523.58.
• Centhaquine citrate The chemical name of Centhaquine citrate is 2–[2–[4–(3–methylphenyl)–1–piperazinyl] ethyl] quinoline citrate (( Figure 1).Centhaquine as a free base is insoluble in water and may not be suitable for developing a formulation for intravenous use, while citrate salt is water soluble.
• Figure 1 Chemical structure of Centhaquine citrate The particle size of the “Centhaquine citrate” can considerably affect its solubility during manufacturing of its lyophilized injectable formulations. The particle size of Centhaquine citrate ranges from 5 to 500 ⁇ m.
• Centhaquine free base is a crystalline anhydrate that is non-hygroscopic. Centhaquine salt is developed and has different polymorphic forms wherein type A is mono-MeOH (Methanol) solvate and can deliquesce when exposed to humidity higher than 75%RH, whereas type B is a non-hygroscopic anhydrate.
• thermodynamic solid form screening was performed under different solvent systems including acetone: water; DMSO (Dimethylsulfoxide): Water; MeOH; IPAc (Isopropyl Acetate); Acetone. Based on the thermodynamic polymorph screening and results type A is MeOH solvate, and it was only obtained from the MeOH system; whereas type B is an anhydrate and obtained from mono-MeOH systems.
• the critical solvent activity was conducted in different systems including either from the following system MeOH/H2O; MeOH/IPAc; MeOH/IPAc/H2O and MeOH/Acetone at RT and 60°C.
• the anhydrate type B is more stable when MeOH activity is equal to or smaller than 0.2 at RT and 0.4 at 60°C.
• To improve the solubility several temperature points were selected and 50°C was chosen for the final first-run crystallization temperature; to improve the yield, several scale batches were set, and the anhydrate phase was obtained with approximate solubility greater than 100 mg/mL.
• the research studies showed that lower doses of Centhaquine increases the blood pressure in animals experiencing blood loss. This prompted a further investigation which demonstrated that Centhaquine is indeed a highly effective resuscitative agent for hypovolemic shock.
• Centhaquine that is freely water soluble is highly desirable for its use as a resuscitative agent in hypovolemic shock (Reniguntala et al., 2015). Centhaquine possesses a distinctive mode of action in comparison to other agents used for resuscitation. It exerts its effects through the stimulation of 2B adrenergic receptors, thereby inducing venous constriction, which enhances the return of blood from the venous circulation to the heart. This increase in blood in the heart causes more blood to be pumped out, due to an increase in ventricular contraction.
• Centhaquine citrate injection 1.0 mg should be administered at a dose of 0.01 mg/kg body weight as an intravenous infusion over 1 hour in 100 mL normal saline in patients of hypovolemic shock.
• the next dose of Centhaquine injection should be administered if systolic blood pressure falls below or remains below 90 mmHg, but not before 4 hours of the previous dose and the total number of doses per day should not exceed 3 doses.
• Centhaquine injection administration if needed, may continue for two days subject to a maximum of 6 doses within the first 48 hrs of treatment.
• the regulatory authorities enforce strict criteria for ensuring the quality of pharmaceutical products.
• API active pharmaceutical ingredients
• tests including assays for purity, testing for related substances, testing for content uniformity, osmolarity testing, and moisture content testing.
• the assay test is used to determine the purity of the test product in comparison to a standard of known purity.
• the related substances test is used to quantify all the impurities present in the product.
• the content uniformity test is conducted to ensure that batches of injectable products contain a uniform amount of drug or API.
• centhaquine citrate may be a more effective cardiovascular agent than Centhaquine (Reniguntala et al., 2015).
• Centhaquine The safety and tolerability of Centhaquine was evaluated in a phase I clinical study (CTRI/2014/06/004647; NCT02408731) using a double-blind, randomized, and placebo-controlled approach.
• the study involved single and multiple ascending doses and demonstrated that healthy male volunteers tolerated the drug well without any serious adverse events. Some non–serious adverse events occurred at 10 to 15 folds higher doses than the therapeutic dose (0.01 mg/kg), including hypotension, high lactic acid, fall in respiratory rate, dryness of mouth, and drowsiness, but they were temporary and resolved without any intervention (Gulati et al., 2016; Gulati et al., 2020). Gulati et al.
• Centhaquine is an efficacious resuscitative agent for treating hypovolemic shock (Gulati et al., 2021).
• the primary objective of the invention is to provide a method for producing an injectable composition comprising lyophilized Centhaquine citrate injection that can be reconstituted using diluent like normal saline (sodium chloride injection 0.9% w/v) or water for injection before administration.
• Another objective is to formulate Centhaquine citrate in such a manner that it manifests high solubility characteristics in aqueous solutions, thereby rendering it suitable for parenteral administration.
• An another objective of the present invention is to introduce an innovative approach to examine Centhaquine citrate, its impurities, and associated compounds without encountering the usual difficulties.
• the present invention is directed to a stable and sterile pharmaceutical formulation that includes lyophilized Centhaquine citrate injection 1.0 mg.
• This formulation is composed of several ingredients, including Edetate Sodium (EDTA), Polysorbate 80 (Tween 80), Mannitol, Sodium Phosphate, Dibasic anhydrous, Sodium citrate dihydrate, Citric acid, and Water for injection (WFI).
• EDTA Edetate Sodium
• Teween 80 Polysorbate 80
• Mannitol Sodium Phosphate
• Dibasic anhydrous Sodium citrate dihydrate
• Citric acid Citric acid
• WFI Water for injection
• Mannitol a sugar alcohol, serves as a bulking agent, while anhydrous Sodium Phosphate Dibasic and Sodium citrate act as buffering agents and regulate the pH of the formulation.
• Citric acid is used to adjust the pH and also act as a preservative.
• the pharmaceutical formulation is thus carefully designed to provide maximum stability, efficacy and safety.
• the lyophilized preparation may contain an appropriate quantity of Centhaquine, although it is desirable for it to contain a therapeutically effective dose of Centhaquine. Specifically, it is preferred that the lyophilized form of Centhaquine citrate be included in the preparation at a concentration of 1.0 mg.
• the Centhaquine in the lyophilized formulation is mainly in the form of Centhaquine citrate.
• the invention provides methods for producing stable and sterile pharmaceutical products containing Centhaquine, specifically as a free base or in the salt form of citrate, acetate, hydrochloride as “Centhaquine citrate” or as “Centhaquine acetate” or as “Centhaquine hydrochloride” but not limited to these and their different polymorphic forms (Type A- mono-MeOH solvate, Type B anhydrate but not limited to these).
• the method for producing a stable, sterile pharmaceutical product containing lyophilized Centhaquine involves preparing a composition containing “Centhaquine citrate or Centhaquine acetate or Centhaquine hydrochloride” and lyophilizing it.
• the method for producing a stable, sterile pharmaceutical formulation containing lyophilized Centhaquine citrate involves preparing a liquid composition containing Centhaquine citrate and excipients in an aqueous solvent. This composition is then cooled and frozen at a temperature of about –40°C for at least 120 to 600 minutes. Afterward, the frozen mixture undergoes a primary drying stage, where a vacuum is applied to remove the aqueous solvent while changing the temperature to a primary drying temperature of –30°C to 25°C for at least 30 to 1320 minutes. Following the primary drying stage, the first intermediate undergoes a secondary drying stage where a vacuum is applied to remove the aqueous solvent from the intermediate.
• the temperature is changed to a first secondary drying temperature of about 40°C for at least 30 minutes, followed by maintaining the intermediate at the same temperature for at least 180 minutes.
• the secondary drying process is then continued again at the same temperature for another 120 minutes.
• the lyophilization cycle took a total of about 93.5 hours to freeze–dry the composition, with primary drying taking about 76 hours and secondary drying taking about 5.5 hours to produce the lyophilized pharmaceutical formulation.
• this method provide a reliable and effective means for producing a stable and sterile pharmaceutical product containing Centhaquine citrate.
• the inventions also provide the method of preparation of lyophilized formulation, which enhances the stability of formulation and the method that will improve the solubility of Centhaquine citrate injection.
• the invention encompasses a technique for treating a medical condition in a patient in need thereof.
• This approach involves administering the suitable therapeutic quantity of the aforesaid drug formulation to the patient after reconstitution in 10 mL of sodium chloride injection (0.9% w/v) or water for injection and then intravenous infusion over 1 hour in 100 ml of normal saline or any other fluids used for resuscitation like crystalloids, colloids, blood products but not limited to these.
• a novel and reproducible HPLC analytical method has been developed and validated for the analysis of Centhaquine citrate drug substance in its lyophilized formulation.
• the method is particularly useful for the identification and quantification of the drug substance (API) in drug product and related substances that emerge during the manufacturing process and during storage period.
• the innovative methodology contributes to the improvement of analytical capabilities for Centhaquine citrate analysis, which can lead to a better understanding of the drug’s behaviour, properties, and potential applications.
• This method employs a mobile phase consisting of one or more liquids, and the proportions of these liquids are modified to a predetermined gradient.
• An additional aspect of the invention involves a technique for evaluating the concentration of impurities in Centhaquine citrate samples or pharmaceutical dosage forms containing Centhaquine citrate. This technique involves analyzing the sample to detect the presence of any of the compounds (impurity) A and B described in the invention.
• the lyophilized pharmaceutical composition comprising about 1.0 mg of Centhaquine citrate; about 1.0 mg of EDTA; about 21.4 mg of polysorbate 80; about 32.40 mg of sodium phosphate dibasic anhydrous; about 6.5 mg of sodium citrate dihydrate; about 150 mg of mannitol.
• the lyophilized pharmaceutical composition wherein the said composition comprises, total impurities not more than 3.0%; or any unspecified impurities not more than 0.5%; or 2–Vinyl quinoline impurity not more than 1.0%, and 1– (3– methylphenyl) Piperazine impurity not more than 1.5%.
• the lyophilized pharmaceutical composition wherein the said composition comprises: total impurities not more than 0.69%; or any unspecified impurities not more than 0.15%; or 2–Vinyl quinoline impurity not more than 0.03% and 1– (3– methylphenyl) Piperazine impurity not more than 0.46%.
• the invention provides a stable, sterile pharmaceutical formulation comprising lyophilized Centhaquine citrate injection, which after its reconstitution with sodium chloride (0.9%) solution or water for injection releases Centhaquine citrate in a therapeutically effective concentration.
• the lyophilized pharmaceutical composition is reconstituted by 0.9% sodium chloride solution or water for injection.
• a reconstituted liquid composition comprising Centhaquine citrate, Ethylene diamine tetra acetic acid – disodium (EDTA), Polysorbate 80, Sodium Phosphate, Dibasic, anhydrous, Sodium citrate dihydrate, Mannitol, Water for injection or 0.9% aqueous sodium chloride solution.
• the reconstituted liquid composition wherein the Centhaquine citrate, EDTA, polysorbate 80, sodium phosphate dibasic anhydrous, sodium citrate dihydrate, and mannitol are provided as a lyophilized powder.
• the reconstituted liquid composition wherein the composition is prepared by reconstituting the lyophilized powder of Centhaquine citrate, EDTA, polysorbate 80, sodium phosphate dibasic anhydrous, sodium citrate dihydrate, and mannitol in water for injection or 0.9% aqueous sodium chloride solution.
• the reconstituted liquid composition wherein the Centhaquine citrate is present in the range from about 0.0004% to about 1.0% w/w; the other water soluble ingredients including EDTA, polysorbate 80, sodium phosphate dibasic anhydrous, sodium citrate dihydrate, and mannitol are present from about 0.0004% to about 90% w/w.
• Table 1 Ingredients along with the composition used in the preparation of lyophilized Centhaquine citrate injection Strength Qty/batch Name of Ingredients Sodium Phosphate Dibasic Anhydrous 32.40 324.00 Sodium citrate dihydrate 6.50 65.00 T formulation of Centhaquine citrate injection 1.0 mg Composition of in- rocess bulk Com osition of te l) f Manufacturing Procedure
• the manufacturing procedure for formulating a lyophilized injection of Centhaquine citrate includes the following steps: Dispense API-Centhaquine citrate, excipients given in Table 1, and primary packing materials. Clean and sterilize filling components with water for injection and autoclave, and wash and sterilize vials in a tunnel sterilizer for depyrogenation.
• Lyophilization The invention also presents a technique for manufacturing a sterile and stable product, which includes lyophilized Centhaquine citrate injection.
• This process involves formulating a mixture of Centhaquine citrate-API and excipients in water for injection and then subjecting it to lyophilization,
• the approach encompasses a set of procedures: a) Formulating a liquid mixture that consists of Centhaquine citrate and an aqueous solvent. b) Precooling the composition or mixture to a temperature of approximately 5°C, c) Freezing the mixture to a temperature of around -40°C to generate a frozen mixture and maintaining the freezing temperature for at least 120 minutes to at least 600 minutes.
• the frozen mixture undergoes a primary drying process, which involves reducing the pressure by applying a vacuum to eliminate the aqueous solvent while adjusting the temperature of the frozen mixture to a primary drying temperature between -30°C to 25°C. This primary drying temperature is maintained for a minimum of 30 minutes and up to 1320 minutes. The entire primary drying process carried out in multiple stages, continued for approximately 76 hours.
• a secondary drying stage By implementing a secondary drying stage, the initial intermediate undergoes a process wherein a vacuum is applied to decrease the pressure to a level sufficient for eliminating any residual aqueous solvent from the intermediate. i.
• first intermediate temperature to a first secondary drying temperature of approximately 40°C, wherein keeping this temperature constant for no less than 30 minutes; and ii.
• the intermediate was maintained at the same temperature for at least 180 minutes.
• iii. The secondary drying process was resumed for another 120 minutes at the same temperature.
• the lyophilized pharmaceutical formulation was obtained after a total of 5.5 hours of secondary drying.
• the composition was freeze–dried in a lyophilization cycle that persisted for about 93.5 hours. After the cycle was finished, the vacuum was released with Nitrogen gas filtered through a 0.2 ⁇ filter, and the vials were partially stoppered under a vacuum of less than 150 mbar.
• a lyophilized Centhaquine-based injectable formulation comprising, an active pharmaceutical ingredient-Centhaquine citrate in the range 0.0004% to about 1.0% w/w; the other water soluble ingredients including EDTA, polysorbate 80, sodium phosphate dibasic anhydrous, sodium citrate dihydrate, and mannitol in the rage of about 0.0004% to 90% w/w; and water for injection.
• Labelling & Packing Label each vial with a printed label and pack the vial as per packing specification. Finished Product release specification. Table 3 outlines the specifications that are required for the final product to meet the desired standards. It provides a detailed description of the necessary characteristics that must be present in the finished product.
• the lyophilized pharmaceutical composition of Centhaquine citrate injection comprises 1.0 mg of Centhaquine citrate; about 1.0 mg of EDTA; about 0.02 mL of polysorbate 80; about 32.40 mg of sodium phosphate dibasic anhydrous; about 6.5 mg of sodium citrate dihydrate and about 150 mg of mannitol.
• the pack or co-pack comprises single or multiple vials containing lyophilized pharmaceutical composition of Centhaquine citrate and single or multiple ampoules of 0.9% sodium chloride aqueous solution, or water for injection.
• a pack comprising a vial containing a lyophilized pharmaceutical composition of Centhaquine citrate.
• the kit or co-pack wherein the kit or co-pack comprises a single vial containing lyophilized pharmaceutical composition of Centhaquine citrate and a single ampoule/vial of 0.9% sodium chloride aqueous solution or water for injection.
• the kit or co-pack, wherein the vial containing a lyophilized pharmaceutical composition of Centhaquine citrate comprises, about 1.0 mg of Centhaquine citrate, about 1.0 mg of Ethylene diamine tetra acetic acid – disodium (EDTA), about 21.4 mg of polysorbate 80, about 32.40 mg of sodium phosphate dibasic anhydrous, about 6.5 mg of sodium citrate dihydrate and about 150 mg of mannitol.
• the packaging configurations as a convenient administration option considered include prefilled standard primary syringes of injection of Centhaquine citrate in a solution, including but not limited to normal saline, water for injection, dextrose solution, or Lactated Ringer’s solution or lyophilized Centhaquine citrate in a cartridge container within a dual-chamber reconstitution system with integrated needle retraction mechanism, wherein the reconstitution system comprises but not limited to normal saline (0.9% Sodium chloride injection), or water for injection, or dextrose solution, or Lactated Ringer’s solution.
• Table 4 outlines the recommended packaging material for Centhaquine citrate. Table 4. Primary Packaging material S.
• the present embodiment provides an improved means for the identification and quantification of one or more substances, such as 1–(3–methylphenyl) Piperazine and 2–Vinylquinoline, within a given sample.
• substances such as 1–(3–methylphenyl) Piperazine and 2–Vinylquinoline
• the conditions for chromatographic analysis of related substances in a sample were established using a specific set of parameters to achieve effective and efficient separation and analysis of related substances in the given sample (Table 7).
• Table 7 Chromatographic conditions (RS) Parameters Condition Gradient program
• the present invention relates to a gradient program utilized in chromatography, which is a technique employed for separating and analyzing mixtures.
• the program provides specific instructions for time, mobile phase A percentage, and mobile phase B percentage to be used during the chromatography process.
• the mobile phase acts as the solvent that passes through the chromatography column and carries the mixture under analysis.
• Mobile phase A and mobile phase B are two distinct solvents mixed in different proportions at specific times to achieve separation of the mixture.
• the analytical method validation summary contains the method, acceptance criteria, and results generated during the analytical method validation of related substance for Centhaquine citrate in the drug product- Lyophilized Centhaquine citrate injection 1.0 mg per vial, which is used for the estimation of known, unknown and total impurities in the drug product for Lyophilized Centhaquine citrate injection 1.0 mg.
• the current innovation is beneficial as it utilizes a selective, sensitive, linear, precise, accurate, and robust method for analyzing related substances in Centhaquine and/or its salts, particularly Centhaquine citrate.
• this invention is incredibly sensitive, making it possible to detect and quantify related substances in Centhaquine and/or its salts at levels well below the established acceptance limits set by WHO and in the ICH Guidelines. Additionally, the proposed method makes it easy to identify and quantify all degradation impurities that arise during the storage of Centhaquine samples. This was determined by conducting forced degradation studies following the ICH QlA Guidelines and validated as per the ICH Q2A Guidelines, which cover various parameters like, system suitability, force degradation, the limit of detection (LOD), the limit of quantitation (LOQ), linearity and range, accuracy, precision (system precision, method precision, and intermediate precision), solution stability, mobile phase stability, and robustness (Table 9). Table 9.
• Parameter Acceptance criteria obtained m n d ts m ne in d ce Parameter Acceptance criteria Results obtained System The standard solution Complies n Parameter Acceptance criteria Results obtained The S/N ratio of LOD Parameter LOD LOQ Parameter Acceptance criteria Results obtained Accuracy The individual % recovery Centhaquine citrate 0 4. 2. 2. 2. 2. 2. 2. 2. 2. 9. e 0 . . . . Parameter Acceptance criteria Results obtained SPL 105. 104. . . 0 . . . . . . Parameter Acceptance criteria Results obtained Precision Parameter Acceptance criteria Results obtained Method The % of unknown ).

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