Sodium Chloride Injection USP Research Articles

Stability of Reconstituted Telavancin Drug Product in Frozen Intravenous Bags

Intravenous (IV) infusions of telavancin for injection are generally administered in-hospital, but in some circumstances they may be administered in an outpatient environment. In that setting, antibiotics may be premixed and frozen. This study determined the chemical stability of nonpreserved telavancin in various commonly used reconstitution diluents stored in IV bags (polyvinyl chloride [PVC] and PVC-free) at -20°C (-4°F) without light. Telavancin (750 mg/vial) was reconstituted with 5% dextrose injection USP (D5W) or 0.9% sodium chloride injection USP (NS) to obtain drug solutions at approximately 15 mg/mL. Infusion solutions of telavancin at diluted concentrations of 0.6 mg/mL and 8.0 mg/mL covering the range utilized in clinical practice were prepared in both PVC and PVC-free IV bags using D5W or NS solutions. The infusion solutions were stored under frozen conditions (-20°C ± 5°C [-4°F ± 41°F]) and the chemical stability was evaluated for up to 32 days. Telavancin concentration, purity, and degradant levels were determined using a stability-indicating high-performance liquid chromatography (HPLC) method. Telavancin IV infusion solutions in D5W or NS at 0.6 mg/mL and 8 mg/mL and stored at -20°C (-4°F) met the chemical stability criteria when tested on days 0, 7, 14, and 32. The assayed telavancin concentration at each time point was within 97% to 103% of the initial mean assay value. The total degradants quantified by the HPLC stability-indicating method did not show any significant change over the 32-day study period. Telavancin IV infusion solutions (in D5W or NS) in both PVC and PVC-free IV bags were stable for at least 32 days when stored at -20°C (-4°F) without light. These results provide prolonged frozen stability data further to that previously established for 7 days under refrigerated conditions (2°C-8°C [36°F -46°F]), and for 12 hours at room temperature when diluted into IV bags containing D5W, NS, or lactated Ringer's solution.

Preclinical pharmacokinetics, biodistribution, radiation dosimetry and acute toxicity studies required for regulatory approval of a Clinical Trial Application for a Phase I/II clinical trial of 111In-BzDTPA-pertuzumab

Introduction111In-BzDTPA-pertuzumab is a novel imaging probe for detecting changes in HER2 expression in breast cancer (BC) caused by treatment with trastuzumab (Herceptin). Our aim was to evaluate the pharmacokinetics, normal tissue biodistribution, radiation dosimetry and acute toxicity of 111In-BzDTPA-pertuzumab in non-tumor bearing mice in order to obtain regulatory approval to advance this agent to a first-in-humans Phase I/II clinical trial. MethodsBiodistribution and pharmacokinetic studies were performed in non-tumor bearing Balb/c mice injected i.v. with 111In-BzDTPA-pertuzumab (2.5MBq; 2μg). The cumulative number of disintegrations per source organ derived from the biodistribution data was used to predict the radiation absorbed doses in humans using OLINDA/EXM software. Acute toxicity was studied at two weeks post-injection of 111In-BzDTPA-pertuzumab (1.0MBq, 20μg) with comparison to control mice injected with unlabeled BzDTPA-pertuzumab (20μg) or Sodium Chloride Injection USP. The dose of 111In-BzDTPA-pertuzumab corresponded to 23-times the human radioactivity dose and 10-times the protein dose on a MBq/kg and mg/kg basis, respectively. Toxicity was assessed by monitoring body mass, complete blood cell count (CBC), hematocrit (Hct), hemoglobin (Hb), serum creatinine (SCr) and alanine aminotransferease (ALT) and by histopathological examination of tissues at necropsy. Results111In-BzDTPA-pertuzumab exhibited a biphasic elimination from the blood with a distribution half-life (t1/2α) of 3.8h and an elimination half-life (t1/2β) of 228.2h. The radiopharmaceutical was distributed mainly in the blood, heart, lungs, liver, kidneys and spleen. The projected whole-body radiation absorbed dose in humans was 0.05mSv/MBq corresponding to a total of 16.8mSv for three separate administrations of 111In-BzDTPA-pertuzumab (111MBq) planned for the Phase I/II trial. There were slight changes in Hb and SCr levels associated with administration of multiples of the human dose in healthy Balb/c mice but no histopathological abnormalities were noted in any tissues. There were no significant differences in body mass between mice injected with 111In-BzDTPA-pertuzumab or control mice. ConclusionPreclinical studies predicted that 111In-BzDTPA-pertuzumab is safe to administer to humans at a dose of 111MBq (5mg). The radiopharmaceutical exhibited preclinical pharmacokinetic, biodistribution and radiation dosimetry properties suitable for advancement to a first-in-humans clinical trial. Advances in knowledge and implications for patient careThe results of these studies supported the regulatory approval by Health Canada of 111In-BzDTPA-pertuzumab for a Phase I/II clinical trial of for imaging the response of patients with metastatic BC to treatment with trastuzumab combined with chemotherapy (PETRA trial; ClinicalTrials.gov identifier: NCT01805908).

Kinevac Stability After Reconstitution with Sodium Chloride Injection USP, 0.9%

Our objective was to compare the stability of Kinevac when reconstituted with sodium chloride injection, USP, 0.9%, versus the manufacturer's recommended sterile water for injection, USP, and to determine the effects on stability of deviating from the manufacturer's recommended methods of product preparation. Kinevac was reconstituted with either sterile water or 0.9% sodium chloride. Triplicate high-performance liquid chromatography was performed on each vial of reconstituted sample at time zero and at time zero plus 8 h. The concentration of each sample, as measured by the peak area, was recorded at each time point. The process was repeated over 4 consecutive days. Kinevac reconstituted with sterile water resulted in the recovery of 89.73% of the time zero concentration after 8 h. Kinevac reconstituted with 0.9% sodium chloride resulted in chemical stability of the injection, with 80.05% recovery of the time zero value after 8 h. Kinevac is more stable when reconstituted with sterile water than when reconstituted with 0.9% sodium chloride. Kinevac should be reconstituted with sterile water for injection as per the manufacturer's instructions.

Stability of Cefepime Hydrochloride Injection and Metronidazole in Polyvinyl Chloride Bags at 4° and 22°–24° C

Cefepime hydrochloride injection 2 g (Maxipime) was mixed with metronidazole injection USP (Flagyl IV ready-to-use, 500 mg/100 mL) and metronidazole hydrochloride IV (Flagyl HCI IV, 500 mg) reconstituted with 0.9% sodium chloride injection USP and/or 5% dextrose injection USP to yield cefepime concentrations of 2, 1, 0.5, and 0.25 g and 500 mg metronidazole per 100 mL of solution. The mixtures were stored in polyvinyl chloride bags up to 168 hours at 4°C and at 22°–24°C. Cefepime and metronidazole mixtures in metronidazole injection USP were stable up to 168 hours and 96–168 hours, respectively, stored in PVC bags at 4°C. The 2.5 mg/mL cefepime and 5.0 mg/mL metronidazole mixtures were stable up to 8 and 72 hours, respectively. Identical mixtures stored at 22°–24°C were stable up to 8–48 and 12–24 hours for cefepime and metronidazole, respectively. Cefepime and metronidazole mixtures in metronidazole HCl IV reconstituted with 0.9% sodium chloride injection USP were stable for 24–168 hours, respectively, stored in PVC bags at 4°C. Identical mixtures of cefepime and metronidazole stored at 22°–24°C were stable for 8–24 and 24–168 hours, respectively. Cefepime and metronidazole mixtures in metronidazole HCl IV reconstituted with 5% dextrose injection USP were stable for 8–48 and 81–68 hours, respectively, stored in PVC bags at 4°C. Identical mixtures of cefepime and metronidazole at 22°–24°C were stable for 8–12 and 168 hours, respectively. In general, cefepime and metronidazole controls were more stable than the mixtures.

Solution conformation of model polypeptides with the use of particle beam LC/FT-IR spectrometry and electrospray mass spectrometry

Solution conformations of the polypeptides β endorphin ( β-END) and a cysteine peptide (CYSP) were investigated with the use of particle beam LC/FT-IR spectrometry. Gradient elution HPLC with mobile phases that contained acetonitrile with 0.1% TFA (v/v) and 0.1% aqueous TFA (v/v) were used. The conformations of both polypeptides were studied in 0.9% sodium chloride injection USP, 5% dextrose in water injection USP and sterile water for injection USP. Additional conformational studies over a pH range of 2–10, temperatures of 25, 50, 75 and 100°C and after storage for 24 h were investigated. The studies indicated that the two polypeptides did not behave similarly under identical conditions. It was observed that both β-END and CYSP had slightly different conformations in the various parenteral solutions. It was also shown that the conformation of CYSP changed with both pH and temperature while β-END was conformationally stable to both temperature and pH. The identity of the peptides and the conformationally sensitive charge-state intensities of the peptides were investigated with electrospray ionization mass spectrometry (ESI/MS). The combination of IR and MS data allowed an estimation of solution effects on the conformations of the model polypeptides.

HPLC ANALYSIS OF A MEROPENEM-OFLOXACIN MIXTURE IN INTRAVENOUS SOLUTIONS USING A NONPOROUS OCTADECYLSILANE COLUMN

A stability-indicating High Performance Liquid Chromato-graphy (HPLC) method utilizing nonporous silica particle technology has been developed for the assay of meropenem and ofloxacin from 5% dextrose in water injection USP and 0.9% sodium chloride injection USP. The separation and quantitation of the mixture were achieved on a column packed with nonporous silica particles chemically bonded with octadecylsilane (3.0 (μm particles) using a mobile phase of 94:6 v/v 15 mM potassium dihydrogen phosphate buffer (pH 2.7)-methanol at a flow rate of 0.6 mL/min with UV detection at 270 nm. The separation was achieved in less than 4 min. Meropenem and ofloxacin were subjected to acid, base, peroxide, and ultraviolet degradation and monitored using photodiode detection. None of the products of degradation showed any interference with the peaks of interest. Standard curves were prepared and correlation coefficients were ≥ 0.999 for both compounds. Precision expressed as %RSD was ≤ 2.0% for both analytes. The limits of detection at a signal-to-noise (S/N) ratio of 3 for meropenem and ofloxacin were 312.5 and 300 ng/mL, respectively, using a 10 μL injection.

HPLC Determinations of Doxorubicin with Selected Medications in 0.9% Sodium Chloride Injection USP

High performance liquid chromatographic methods have been developed for the assays of mixtures containing doxorubicin-morphine, doxorubicin-granisetron, and doxorubicin-cyclophosphamide in 0.9% sodium chloride injection USP. The separation and quantitation of each mixture were achieved on octylsilane columns at ambient temperature using a mobile phase of aqueous sodium dihydrogen phosphate - acetonitrile at a flow rate of 1.0 mL/min with UV detection. The separations were achieved within 13 min. The methods showed linearity for the analytes in their respective calibration ranges. Accuracy and precision were in the 0.1–3.3% and 0.2–3.1% ranges, respectively, for the various analytes.

Solution conformation of model peptides with the use of particle beam LC/FT-IR spectrometry and electrospray mass spectrometry

Solution conformations of the peptides angiotensin I (Ang I) and POMC-X (an octapeptide fragment of proopiomelanocortin) were investigated with the use of particle beam liquid chromatography/Fourier transform infrared (LC/FT-IR) spectrometry. Gradient elution high-performance liquid chromatography (HPLC) with mobile phases that contain acetonitrile, 2-propanol, 0.1% heptafluorobutyric acid (HFBA) and 0.1% trifluoroacetic acid (TFA) were used. The conformations of both peptides were studied in 0.9% sodium chloride injection USP, 5% dextrose in water injection USP and sterile water for injection USP. Additional conformational studies over a pH range of 2–10, to a temperature of 75°C and after a storage time of 24 h were investigated. The studies indicated that the two peptides do not behave similarly under identical conditions. It was observed that both Ang I and POMC-X had slightly different conformations in the various parenteral solutions. It was also shown that the conformation of Ang I changed with both pH and temperature while POMC-X was conformationally stable to both temperature and pH. The identity of the peptides and the conformationally sensitive charge-state intensities of the peptides were investigated with electrospray ionization mass spectrometry (ESI/MS). The combination of infrared and mass spectrometric data allowed a thorough estimation of solution effects on the conformations of the model peptides.

HPLC Determination of Idarubicinetoposide and Idarubicin-Ondansetron Mixtures in 0.9% Sodium Chloride Injection USP

High performance liquid chromatographic methods have been developed for the assays of idarubicin-etoposide and idarubicinondansetron mixtures in 0.9% sodium chloride injection USP. The separation and quantitation of the idarubicin-etoposide mixture was achieved on an octylsilane column at ambient temperature using a mobile phase of 73:27 v/v 0.02 M aqueous monobasic sodium phosphate - acetonitrile at a flow rate of 1.0 mL/min with UV detection at 254 nm. The separation was achieved within 13 min. The method showed linearity for idarubicin hydrochloride and etoposide in the 2–32 and 10 – 160 μg/L ranges, respectively. Accuracy and precision were in the 0.1 – 2.9% and 0.1 – 2.1% ranges, respectively, for both analytes.

HPLC Determinations of Ondansetron with Selected Medications in 0.9% Sodium Chloride Injection USP

Abstract High performance liquid chromatography procedures have been developed for the assay of ondansetron-selected medications in 0.9% sodium chloride injection USP. The separation and quantitation of each mixture were performed on either an underivatized silica column or a bonded phase column at ambient temperature using either a methanol or acetonitrile-phosphate buffer mobile phase in the 4–5.4 pH ranges with detection set at 254, 233 or 210 nm. The separations were usually achieved within 20 min. Linearity, limit of detection, retention and tailing factors, resolution, accuracy and precision were calculated for each mixture.

Chemical stability and adsorption of atracurium besylate injections in disposable plastic syringes.

Atracurium besylate (AB) is supplied as a sterile, non-pyrogenic aqueous solution for intravenous use. Hospitals pre-fill disposable plastic syringes with these solutions so that they are ready for immediate use when required. Drug loss due to potential adsorption on to the plastic material of the syringes has not been studied. Atracurium is also administered by intravenous infusion using a diluted solution in either 5% dextrose injection (USP) or 0.9% sodium chloride injection USP. Drug solutions not used within 24 h are usually discarded, resulting in tremendous waste. The purpose of these investigations was to determine the adsorption behaviour of atracurium when stored in plastic syringes, and to study the degradation of atracurium in i.v. fluids. For the adsorption study, 10 mg/ml solutions were used, whereas the diluted infusion solutions were prepared to contain 0.5 mg/ml of atracurium. Drug degradation was monitored using a stability-indicating high-performance liquid chromatography method. Degradation studies were conducted at 5 degrees C, 25 degrees C and 40 degrees C. Refrigeration was observed to improve drug stability. The manufacturer's recommended expiry period was too conservative. Storage at room temperature for up to 6 weeks can be safely recommended, without significant loss of chemical stability.

Stability of frozen solutions of cefazolin sodium

The stability of frozen solutions of cefazolin sodium was investigated in nine commonly used diluents at concentrations of 1 g with 2.5 ml, 500 mg with 100 ml and 10 g with 45 ml in both glass and polyvinylchloride plastic containers. The diluents were: Water for Injection USP; 0.9% Sodium Chloride Injection USP; 5% Dextrose Injection USP (D5W); D5W with 0.02% sodium bicarbonate; D5W in Lactated Ringer's Injection USP; Lactated Ringer's Injection USP; Ionosol B in D5W; Normasol M in D5W; and Plasmalyte in D5W. Frozen cefazolin sodium solutions, containing Water for Injection USP, 5% Dextrose Inection USP or 0.9% Sodium Chloride Injection USP as the diluents, retained more than 90% of labeled potency for up to 26 weeks when frozen within one hour after reconstitution and held at -10 C or -20 C. Frozen cefazolin sodium solutions, made with other diluents, were stable for up to four weeks when frozen within one hour after reconstitution and held at -10 C.

Compliance with USP osmolarity labeling requirements

In view of the USP requirement that the label of certain parenteral products contain the osmolarity of the solution, actual and theoretical osmolarity values for six preparations were determined, and the extent of any deviation was noted. Osmolarity values were determined experimentally by osmometry and converted to osmolarity values for six products: Calcium Chloride Injection USP, Dextrose Injection USP, Mannitol Injection USP, Potassium Chloride Injection USP, Sodium Bicarbonate Injection USP, and Sodium Chloride Injection USP. Theoretical values were calculated according to a standard equation based on the mass of the substance per liter of solution. The most substantial deviations between actual and theoretical osmolarity values occurred with the calcium chloride, sodium bicarbonate, potassium chloride and dextrose solutions. It is proposed that the technology for making osmotic measurements which exists in the industrial setting should be used to provide clinical practitioners with accurate and actual values. It is also urged that the USP specify a procedure for measuring osmolality and calculating actual osmolarity.