Short-term Stability Studies Research Articles

Gadolinium incorporated reconstituted chylomicron emulsion for potential application in tumor neutron capture therapy

Gadolinium (Gd) neutron capture therapy (NCT) is currently under development as a potential approach for tumor therapy. Nanoparticles have been suggested as a potential delivery system to carry or target Gd to tumors for thermal or epithermal neutron irradiation. The reconstituted chylomicron emulsion is an artificial chylomicron remnant prepared using commercially available natural and biocompatible lipids. We proposed to use this nanometer-scale emulsion to deliver Gd to solid tumors by modifying the surface of the emulsion. A lipophilic Gd compound, gadolinium acetylacetonate (GdAcAc), was incorporated into the emulsion, resulting in a final pure Gd concentration of more than 1 mg/mL. The apparent solubility of GdAcAc was enhanced by about 6000-fold by this incorporation. The emulsion particles were shown to be stable in a two-week short-term stability study when stored at 4 °C. In addition, no extensive particle aggregation was observed when the emulsion particles were incubated in simulated biological media such as serum. Also, GdAcAc does not significantly ‘leak’ out from the emulsion particles. Only ∼5% was released in 20 h in a SDS (0.5% w/v) in phosphate buffered saline (pH 7.4, 10 mM) medium. Finally, the emulsion particles were coated with polyethylene glycol (PEG), and injected into Balb/C mice via the tail vein. A significant proportion (71.6±18.4%) of the PEG-coated, GdAcAc-incorporated emulsion remained circulating in the blood 5 h after the injection, while the PEG-free emulsion was mainly accumulated inside the liver. This chylomicron emulsion may be used to deliver Gd into solid tumors for NCT.

Preparation, Characterization, and Stability of Liposome-Based Formulations of Mitoxantrone

The preparation, characterization, and stability of lyophilized liposome-based formulation of mitoxantrone was investigated. Mitoxantrone was entrapped inside small, unilamellar liposomes composed of dioleoylphosphocholine (DOPC), cholesterol, and cardiolipin. The mean vesicle size and drug entrapment efficiency of the liposomes were ~ 150 nm and ~ 99%, respectively. Less than 1% of drug was lost and mean vesicle size remained unchanged after sterile filtration. The pre-lyophilized (pre-lyo) formulations were characterized by a differential scanning calorimetric (DSC) method. Results showed that the glass transition temperatures (Tg′) increased as the molar ratios of sucrose:lipid and trehalose:lipid in the formulations were increased. The maximum Tg′ of the pre-lyo formulations containing 10:1 sucrose:lipid and trehalose:lipid molar ratios were − 37°C and − 41°C, respectively. After reconstitution of the lyophilized cake of the sucrose-containing formulation, the mean vesicle size was comparable to pre-lyo liposome size. In vitro release studies showed that less than 2% of mitoxantrone was released after an extensive dialysis against phosphate buffered saline (PBS) at 37°C, indicating that the mitoxantrone was highly associated and retained inside the liposomes. Short-term stability studies of the sucrose-containing formulations revealed that the reconstituted and eight-fold diluted formulations were stable for up to 8 hours at room temperature. Long-term stability studies of lyophilized liposomal mitoxantrone showed that the lyophilized formulation was stable for up to 13 months after storage at refrigerated condition.

Element selective characterization of stability and reactivity of selenium species in selenized yeast

The concerted application of element specific atomic spectral detection for chromatographic eluent monitoring allows previously unexploited qualitative and quantitative analytical concepts to be developed for the determination of selenium species. Selenium speciation is vital in order to better understand its metabolism and biological significance in clinical chemistry, biology, toxicology, and nutrition. Fluoroacid ion pair HPLC with ICP-MS detection and GC derivatization with atomic emission detection (AED) together aid analysis and elucidation of reaction pathways of selenium compounds in high selenium enriched yeast, as used widely in nutritional and clinical cancer preventative studies. Comparisons between currently produced and archived selenized yeasts show major differences in speciation. The formation of selenomethionine selenoxide and the identification of Se–S bonded S-(selenomethyl)-cysteine in archived nutritional yeast may be important for short and long term stability and nutritional activity studies.

Submicron emulsions as drug carriers: Studies on destabilization potential of various drugs

Few drugs have been successfully formulated as submicron emulsions. The physicochemical stability of submicron emulsions on admixture of drugs is the main factor limiting a wider use of this type of vehicle for parenteral or other routes of administration. In a short-term stability studies we have investigated 35 drugs with regard to their compatibility with 20 or 5% parenteral fat emulsions. The study has shown that interaction of drugs with submicron emulsions is complex in nature. Taking into consideration the physicochemical properties of a drug e.g. lipophilicity or ionization, it is difficult to predict changes in the physical stability of the system. If destabilization occurs it is maximal at saturated concentrations and the presence of even significant amounts of the solid phase formed by undissolved drug does not influence the short-term stability of the system. Due to the increased ratio of emulgator to oil, emulsions containing 5% of oily phase are less susceptible to destabilization than 20% emulsions.

Pramlintide injection drug product robustness studies.

The article examines the effects of temperature excursions and actual dose withdrawal on the quality of pramlintide injection, a multidose liquid parenteral formulation. Studies were designed to demonstrate product robustness under conditions that may occur during patient use. Pramlintide %Purity was determined by two high-performance liquid chromatography (HPLC) methods, a reversed-phase (RP-HPLC) and a strong-cation exchange (SCX-HPLC) method. A second RP-HPLC method was used to determine pramlintide potency and the concentration of the m-cresol preservative. Antimicrobial preservative effectiveness testing was per USP and European Pharmacopeia (Ph. Eur.). Short-term stability studies were undertaken to probe the effects of the following conditions: 5 degrees C to 40 degrees C and 5 degrees C to -20 degrees C temperature cycling over 10 days; once daily or four-times daily dose withdrawal over 12 or 42 days; and combined 30 degrees C storage and four-times daily dose withdrawal over 42 days. In all cases, pramlintide %Purity and potency values remained essentially unchanged or unchanged relative to controls. Similarly, product appearance, and m-cresol concentration and preservative effectiveness were not significantly affected by the stress conditions used in the 5 studies. Pramlintide injection drug product is extremely robust to challenging stress conditions that may occur during patient use of this multidose product for chronic administration.

Measurement of felbamate by wide-bore capillary gas chromatography and flame ionization detection

Felbamate, a newly developed antiepileptic agent, has been demonstrated to control partial and generalized seizures effectively. We have developed a gas-chromatographic method for the determination of felbamate, using a wide-bore capillary column, a flame ionization detector, and a simple extraction procedure. The assay day-to-day precision (n = 20) was 5.2% and 3.6% for drug concentrations of 50 and 150 mg/L, respectively; average recovery over a wide range of felbamate concentrations was 95%; the detection limit was 5 mg/L; and assay linearity extended to 300 mg/L. Although 9 of the 27 drugs tested were coextracted with felbamate, they exhibited significantly different retention times and showed no interference. A short-term stability study showed that plasma felbamate is stable at 4, -20, or -78 degrees C for at least 1 month. Plasma felbamate concentrations in 66 pediatric patients ranged from 7 to 154 mg/L (mean +/- SD 44 +/- 24.7). We consider the method ideally suited for therapeutic monitoring of plasma felbamate concentration.

Stability studies of vitamins in three food reference materials

Stability in storage and shipment of retinol, α-tocopherol, vitamins B1, B2 and C in three foods was studied to assess the feasibility of certifying the vitamin content of three food RMs, whole milk powder (CRM 380), pork muscle (CRM 384) and freeze-dried haricot beans (CRM 383); these were recently certified for major dietary components and major elements. Interpretation of the long-term stability data was complicated by a dominant analytical variability over the measurement period. The long-term stability study (24 months) gave evidence of deterioration of vitamin B2 in pork muscle. The other vitamins studied seemed to be acceptably stable at −18°C and +4°C. Additional studies showed stability of retinol in milk powder for 34 months and of vitamin C in haricot beans for 31 months at −18°C and +4°C. Long-term storage seems to be possible at a temperature not higher than +4°C except for vitamin B2. A short-term stability study at +25°C and +30°C for 6 weeks showed acceptable stability of retinol and α-tocopherol in milk powder (CRM 380) and of vitamin C in haricot beans (CRM 383). However, storage at +42°C induces degradation of retinol, α-tocopherol and vitamin C.

Physico-pharmaceutical characteristics of steroid/crosslinked polyvinylpyrrolidone coground systems

A high-energy milling technique was used for improving the biopharmaceutical properties of 6-methylenandrosta-1,4-diene-3,17-dione (FCE24304), an aromatase inhibitor, slightly soluble in water. Cogrinding with crosslinked polyvinylpyrrolidone (PVP-CL) was evaluated using different ratios of drug/polymer and powder/grinding media. The improved dissolution systems were then analysed and discussed in terms of the residual crystallinity of the drug (by DSC and X-ray), wettability, particle size analysis and dissolution rate behaviour. An accelerated short-term stability study was then carried out on a 1:3 w/w system.

Stability studies on steroidal drug/β-cyclodextrin kneaded systems

6-Methylenandrosta-1,4-diene-3,17-dione (FCE24304), an aromatase inhibitor, is characterised not only by poor solubility in aqueous media and slow dissolution rate, but also by low chemical stability due to possessing conjugate double bonds. Several approaches have already been evaluated for improving both the biopharmaceutical properties and chemical stability of drugs in a particular way by the use of β-cyclodextrin. An accelerated short-term stability study on FCE24304β-cyclodextrin kneaded systems, prepared using two different molar ratios, was carried out and the systems evaluated by HPLC, DSC and X-ray difiractometry techniques and correlated with dissolution rate behaviour. A tablet formulation with a 1:2 molar ratio of the FCE24304/β-cyclodextrin complex is now under development.

Characterization of Proliposomes

Photographic evidence of the process of proliposone hydration is provided together with comprehensive particle size analysis of both hydrated dimyristoylphosphatidylcholine:dimyristoylphosphatid-ylglycerol:ergosterol: amphotericin B proliposomes and egg lecithin:ergosterol:amphotericin B proliposomes using photon correlation spectroscopy and Coulter Counter analysis. Proliposome particle size and the temperature during hydration have been shown to have little effect on subsequent liposome size. A short term stability study of proliposomes indicated that only minor changes in the size distribution profile of the hydrated product are apparent after storage at 20°C for 9months. Furthermore, no drop in amphotericin B potency was noticed over a 6-month period.

Stability of the 6,14-Endo-Ethanotetrahydrooripavine Analgesics: Acid-Catalyzed Rearrangement of Buprenorphine

Buprenorphine (I), a member of the 6,14-endo-ethanotetrahydrooripavine series of analgesics, undergoes an acid-catalyzed rearrangement reaction when exposed to acid and heat. The product was shown by 1H-NMR and GC-MS to have undergone overall elimination of a molecule of methanol with concurrent formation of a tetrahydrofuran ring at C(6)-C(7) of I. Short-term stability studies across a wide range of pH and temperature conditions indicate that I is stable in aqueous solution at pH > 3 for 24h at 36-38°C. Under the more extreme conditions of the autoclave, significant loss of I occurred. Long-term stability studies (10 weeks) of I in aqueous solution (pH 1 and pH 5) at 0-4°C and 26-28°C indicate only minor conversion (4%) to the rearrangement product. Eight other 6,14-endo-ethanotetrahydrooripavine derivatives were subjected to extremes of acid (pH 0) and temperature (autoclave) to determine if similar rearrangement reactions occur. GC-MS indicated that hydrolysis products were produced whose spectra were consistent with the proposed rearrangement structures.

Short‐ and long‐term stability studies on four lyophilised and one cell‐associated turkey herpesvirus vaccines against marek's disease of chickens1

One cell-associated and four lyophilised turkey herpesvirus (HVT) vaccines of different manufacturers were investigated comparatively in respect of the stability of their infectivity. All titrations were performed in primary chicken embryo fibroblast cell cultures and repeated seven times. The obtained data were computerised and statistically analysed. The long term stability study employed vaccine ampoules containing only lyophilised HVT. After appropriate storage in a refrigerator (4 degrees C) of all tested vaccine ampoules for 1 year no drop of titre was found. In contrast, storage at room temperature (24 degrees C) resulted in a loss of about 50% of the infectious units of HVT by 4 months. Marked differences between the products of different manufacturers were noted after 4 weeks of storage at 37 degrees or 45 degrees C. The infectivity dropped to values between 1/10 to 1/100 and 1/100 to 1/300, respectively. In the short term stability study cell-associated and lyophilised vaccine virus was resuspended in the manufacturer's diluent and maintained at temperatures of 4 degrees , 24 degrees , 37 degrees and 45 degrees C. The infectious units were titrated at 0, 2, 4, 6, 8 and 24 hours for estimation of the half life of the infectivity of HVT. The half life of infectivity of HVT at 4 degrees C was for three vaccines approximately 5 hours and for two vaccines between 1 and 3 hours. With increase of temperature the loss of infectivity increased resulting in half life times close to 1 hour at 45 degrees C.

Dissolution Rates of Hydrocortisone and Prednisone Utilizing Sugar Solid Dispersion Systems in Tablet Form

The utilization of ternary sugar solid dispersion systems and the incorporation of these systems into tablet dosage forms were investigated. The dispersion systems were prepared by the fusion method using 50% sucrose–50% mannitol and 50% sorbitol–50% mannitol. Other systems investigated utilized sorbitol, mannitol, and polyethylene glycol 6000 for comparison. The drug component was hydrocortisone or prednisone. The results from a modified NF XIII dissolution rate determination revealed that the mannitol system had the fastest dissolution rate, followed by sorbitol–mannitol, sucrose–mannitol, sorbitol, and, finally, polyethylene gylcol 6000. The corticosteroids were stable and did not decompose during preparation of the dispersion systems or direct compression of the tablets. A short-term stability study revealed that the tablets retained their fast dissolution rates and that the tablet characteristic tests, i.e., tablet hardness, remained unchanged. The use of sugar combinations overcame some difficulties previously reported with single sugar systems.

Orodispersible Tablets of Carbamazepine Prepared by Direct Compression Method Using 3<sup>2</sup> Full Factorial Design

Orodispersible tablets of carbamazepine were prepared with a view to enhance patient compliance by direct compression method using 3² full factorial design. Crospovidone (2-10% w/w) was used as superdisintegrant and microcrystallinecellulose (0-30% w/w) was used as diluent, along with directly compressible mannitol to enhance mouth feel. The tablets were evaluated for hardness, friability, thickness, drug content uniformity, in vitro dispersion time, wetting time and water absorption ratio. Based on in vitro dispersion time (approximately 10 s); the formulation containing 2% w/w crospovidone and 30%w/w microcrystallinecellulose was found to be promising and tested for in vitro drug release pattern (in pH 6.8 phosphate buffer), short-term stability (at 40º/75 % RH for 3 w) and drug-excipient interaction. This formulation showed four-fold faster drug release (t25%) compared to the conventional commercial tablet formulation. Short-term stability studies on the formulation indicated that there are no significant changes in drug content and in vitro dispersion time (p < 0.05).Key words: Orodispersible tablets, carbamazepine, crospovidone, micro crystallinecellulose, 3² full factorial designDOI = 10.3329/dujps.v7i1.1199Dhaka Univ. J. Pharm. Sci. 7(1): 1-5, 2008 (June)

The Effect of Cast Films of Bovine Mucin and Prosopis Gum Containing a Cicatrin® Powder on Wound Healing

Orodispersible tablets of carbamazepine were prepared with a view to enhance patient compliance by direct compression method using 3² full factorial design. Crospovidone (2-10% w/w) was used as superdisintegrant and microcrystallinecellulose (0-30% w/w) was used as diluent, along with directly compressible mannitol to enhance mouth feel. The tablets were evaluated for hardness, friability, thickness, drug content uniformity, in vitro dispersion time, wetting time and water absorption ratio. Based on in vitro dispersion time (approximately 10 s); the formulation containing 2% w/w crospovidone and 30%w/w microcrystallinecellulose was found to be promising and tested for in vitro drug release pattern (in pH 6.8 phosphate buffer), short-term stability (at 40º/75 % RH for 3 w) and drug-excipient interaction. This formulation showed four-fold faster drug release (t25%) compared to the conventional commercial tablet formulation. Short-term stability studies on the formulation indicated that there are no significant changes in drug content and in vitro dispersion time (p < 0.05).  Key words: mucin, Prosopis gum, cicatrin, healingDOI = 10.3329/dujps.v7i1.1200Dhaka Univ. J. Pharm. Sci. 7(1): 7-10, 2008 (June)