qupv 5 (TAP, MINERAL, AND DISTILLED watER): Garcia cali reported the stability of eaptopril 1 mg/ml in tap ‘tater, mineral water, and distilled water stored at 4 and 25°C jn PVC plastic containers and protected from exposure to tight lo disiled water alone, HPLC analysis found that cap- topril was stable for 30 days stored at 4°C but was much les suableat 25°C. Captopril was also much les stable in tap and inineral water at either temperature, Incorporation of ede- tate disodium, ascorbic acid, sodium ascorbate, or sodium snetbisulite all reduced captopril stability in aqueous sola ‘ons compared tothe stability in distilled water alone Topical Haungetal” evaluated the stability ofcaptopilinconporated ino 5% topics gl formations for transdermal delivery. @ Carbamazepine Properties Carbamazepine is white to off white crystalline power >It isrported tobe biter, with an unpleasant aeraste™ Solubility Carbamazepineisinsolublein waterbut soluble in ethanol? General Stability Considerations Carbamazepine tablets should be stored in tight containers {gassisecommended), preferably at controlled room tem- ‘ratte; they should be protected from temperatures above [0°C. The able bioavailability may be reduced one-third by nnisture due to formation ofa dihydrate that causes tablet hardening. Consequently, containers should be ept tightly closed and stored away from areas subjected to high humid~ 4 (ie, bathrooms). Use of silica go sachets also has been suggested Carbamazepine suspension should be stored in tight, lghtresitant containers at temperatures not exceding 30°C The suspension also should be proteced from freezing.** Katinen etal. reported carbamazepine concentration ‘aration in frozen liquid samples possibly because of pre- ‘ition of the drug at low temperature and inadequate ‘eistluton ater rewarming Sorption Thelosofearbamazepine from the oral suspension to naso- strc feeding tubes was evaluated by Clark-Schmidt et al.” Samples of 10 mi of carbamazepine suspension (Tegretol ib-Geigy) 100 mg/5 ml. were drawn into syringes and ‘Administered undiluted or diluted with an equal volume of Ash solution (sterile water, 0936 sodium chloride, 5% dex- os) through adult (12 French, Seamless Division of Pro- ‘sional Medical Services) or pediatric (5 French, American ~— Carbamazepine 101 ‘Several formulations were used with 596 carboxymethyleel- lulose and hydroxymethylcellulose gels having shelf lives of 29 and 27 days, respectively, at 30°C and 70%6 relative humic ity. These were substantially better than absorption cream base (seven days) or topical solution (5.6 days). The addition of 19% EDTA to the carboxymethylcellulose gel formulation extended the shelf life to 320 days; if 1% acetic acid was also incorporated, the shelflife became 418 days. Compatibility with Other Drugs Huang etal evaluated the stability of captopril incorpo- rated into 59 topical gel formulations with the addition of 0.2% dobetasol and 0.05% diphenhydramine. No differences in oxidative ate constants were found wth ether agent, ind cating they are compatible with captopril Pharmaseal Co.) nasogastric tubes. After the suspension was administered, the nasogastric tubes were flushed twice with ‘50 mL ofthe flush solution. Efluent samples were analyzed for carbamazepine by HPLC. Carbamazepine losses were genet~ ally greater in the samples administered undiluted, the worst providing only 76% ofthe intended dose. Losses in the diluted sample were usually ess than 10%, with about 90 to 989% of the dose being delivered. Tube size made little difference. The undiluted suspension appears to stick to the tube walls to a ‘greater extent than does the diluted suspension. The authors recommended diluting the suspension with an equal volume ‘ofdiluent before administering, followed by adequate flushing, Stability Reports of Compounded Preparations Oral STUDY 1 REPACKAGED): Lowe etal. evaluated the stability of commercial carbamazepine suspension (Tegretol, Ciba- Geigy) 20 mg/m repackaged in several types of single-dose containers in 2- and 8-ml. portions. Containers evaluated Included glass orl syringes (2 ml. in S-m. amber Solopak syringe only) amber gas vials (Solopak), amber polypropyl- ene oral syringes (Baxa), and polypropylene vial (Solopak). ‘The sample containers were capped, stored at 24°C, and exposed to fluorescent light for 12 weeks. Carbamazepine content was assessed usinga stabilty-indicating HPLC assay. No changes in odor, color, suspension consistency, or flow ‘were observed. However, significant los of drug content (about 20 to 30%) occurred inall containers within 12 weeks, Although the results were somewhat erratic, the authors con. cluded thatthe repackaged suspension was stable for eight ‘weeks at room temperature STUDY 2 (XTEMPORANEOUS): Burckart et al. reported on. testability ofan extemporancously prepared carbamazepine102 Carbamazepine suspension, Carbamazepine 200-mg tablets (Tegretol, Ciba- Geigy) were crushed to fine powder and incorporated into four suspending vehicles, sorbitol 70%, simple syrup, and two custom vehicles, at a concentration of 200 mS ml. (Table 20) The suspensions were packaged in amber bot- {les and stored at 4,25, and 37°C. In addition, the suspen sions were packaged in unit-dose syringes and stored at 4°C only. Carbamazepine was assessed using a stability~ indicating enzyme-multiplied immunoassay (EMIT, Syva) cover 90 days, The refrigerated sorbitol suspension froze but resus pended when thawed and shaken vigorously. The suspension in simple syrup separated over 90 days, bu it resuspended when shaken vigorously. Particle size in these two suspen: sions increased during storage from two-to fourfold. How- ever, carbamazepine concentrations emiined above 90% ‘of inital concentration in both suspensions throughout the study. In custom vehicle 1, the suspension became viscid and dificult to pour; foam formed when the suspension was shaken. Furthermore the carbamazepine concentra tions were somewhat erratic. In custom vehicle 2, the su5- pension was homogeneous, easy to pou, and produced less foam upon shaking. Also, carbamazepine concentrations ere above 909% ofthe initial concentration in all samples throughout the study. The authors concluded that either simple syrup or custom vehicle 2 was an acceptable vehicle for carbamazepine suspensions STUDY 3 (EXTEMPORANEOUS):Jover Boll et l™ eval ated the stability of carbamazepine 25 and 50 mg/m oral suspensions prepared from bulk powder. The carbamaze- pine powder was triturated using a mortar and peste and Incorporated into an equal parts mixture of Ora-Sweet SF and Ora-Plus (Paddock). The oral liquids were packaged in amber glass containers and stored at room temperature (24 10 27°C) for 6 months. The orl liquids were nese pil 45 and didnot change during storage. The physical attributes of. TARLE20. Custom Vehicles for Carbamazepine Suspensions™ ‘Component Vehicle Vehicle? Sucrose 25g 958 Sorbitol 70% som 40mL Glycerin 125m ASML Saceharn sodium 250m 170mg. Methylparaben 500mg 340mg Methyletaiose 400 698 478 “Methyleluose 4000 aig 2g FD&C yellow 730mg slOmg emo ime for sm. Tmt Purified water 9 500m__—__500mL ccd powder sinter ctumnepneos bon el after storage at room temperature for 6 months, 7 stuy 4: Polonin etal evaluated carbamazepine 25 ny oralsspension for stability at controled refrigerated 299) and controlled rom (2010 25°) temperatureowr agg petiod The suspension had the following formulation, Carbamazepine powder SyrSpend SEPHS 5 300mL Thestated method for compounding was to add the required ‘quantity of carbamazepine powder toa low-actnic bot, then add by volumetric pipette the SyxSpend SP PH un «final volume of 300 mL was achieved. The suspension was assayed at time zero and then split into two diferent bots: ‘one botle ws stored at USP controlled refrigerated tempera. ture and the other botle at room temperature for the dura tion ofthe study. Sampling times were then days 7, 14,30, 60, and 90, each being evaluated by HPLC. Stability indicating studies were performed on the suspension and showed that the suspension was stable for 90 days at controlled refriger- sted and room temperatures. Enteral ‘STUDY : Basset? found reduction inthe bioavalibilty of ‘arbamazepin suspension when given with an enteral prodct (Osmolite Ross) A10 French 104-cm nasogastric eeding tube (Entries, Bosearch) was used to administer carbamazepine Suspension 500 mg/25 mL (Tegretol Ciba-Geigy) both in a fasting stateand with enteral feeding After the carbamazepine losing the tube was lushed with 60 ml. of water. The relive bioavailability of carbamazepine given withthe enteral feed- ing was 90.1% of tat given ina fstng state. StUDY 2: Williams noted decreased absorption from cat= bbamazepine suspension delivered through enteral feeding tubes and cited the need to dilute carbamazepine suspen sion with sterile water or sodium chloride 0.9% to reduce adherence to feeding tubes In addition, it was noted that «lose monitoring of carbamazepine seram concentrations is ‘warranted, Rectal ‘Ammar and Marzouk™* evaluated the stability of earbam- azepine fast-elease polyethylene glycol (PEG) rectal suppos- {ories. The formula tested varied by the molecular weight of the PEG. All ofthe formulas exhibited acceptable hardness solubility time, and conten uniformity. Accelerated stability testing a 30 and 40°C demonstrated that about 210 5% of the drog was lost during the test petod, anInjection {iam ke ther sere drugs shouldbe prepared ina uit Iden aizenvioomentusingappropiatasepicprocercs, pen prepare from nonsterile components, an appropriate Wi afevesterlization method must be employed Jain et al! reported the stability of an extemporane- uly prepared carbamazepine 3.6-mg/ml. injection for- arsed in 50% (wt/vol) sodium sliylate solution, The ecton was sterilized by flation through 0.2m ser ‘foclving resulted in loss of about 16% of the carbam- ‘pepne, Samples of the injection were stored at # and 23°C @§ Carbenicillin Disodium Carbidopa 108 aval as at ltd temperatures About 2 103% carb wre as occed afer 49 dys sored a8 of 23°C ani empersturs of 30 and 60°, 32 0 36% 18s ‘occurred in seven days, accompanied by the formation of a set color The saya xing this formulation as not reported. Compatibility with Other Drugs Mixing chlorpromazine hydrochloride oral solution with carbamazepine orl solution is reported to result inthe for- ‘mation of an orange rubbery precipitate? ml Carbenicillin Indanyl Sodium Properties Carbenciln disodium is a white to almost white hygro- Scope power. Each 11 g ofthe disodium slt is equivalent to 1 gof carbeneillin. Each gram provides 4.7 to 6.5 mEq tf sodium.*Carbenicilin indany sodium also isa white to realy white powder and hasa biter taste? Solubility CCarbenicillin disodium has an aqueous solubility of 1g in 12a its solubility in ethanol is 40 mg/ml.2* The indanyl sodium form is also soluble in water* pH ‘A196 solution of carbenicillin disodium in water has a pH of 65108, while a5 solution has a pH of 5.5 to 7.5? General Stability Considerations Carbenicllin products should be stored in tight containers at controlled room temperature. Inaqueous solution, carbenicilin is subject to hydrolysis ofthe lactam ring, Maximum stability occurs at pH 6.5; the degradation rat increases rapidly asthe pH increases or Carbidopa Properties Carbidopa isa white to creamy or yellowish white odorless or Practically odorless crystalline powder." Carbidopais ava ableas the monohydrate, but the drug potency is express interms of the anhydrous form.? Solubility bidopa is slightly soluble in water nd pra ‘ein ethanol and acetone. tis reey soluble in 3N hydro- ehlorc acid ly insolu- decreases from 6.5. At pH 2, the halflife of carbenicillin disodium at 21°C is 140 minutes.” Stability Reports of Compounded Preparations Ophthalmic Ophthalmic preparations ike other sterile drugs, should be prepared na suitable clean air environment using appropriate aseptic procedures. When prepared from nonsterile compo ems, an appropriate and effective sterilization method must beemployed. EL-Shattawy"* evaluated the stability of 0.39% carbes cilin disodium in 36 formulations of ophthalmic ointment bases. Bach of 18 different formulations was duplicated with 0.1% parabens (methylparaben-propylparaben, 2:1) as pre servativesand with 0.196 tocopherylacetateasan antioxidant. ‘The ointments were stored at 5°C for eight months. Carben- icillin activity was assessed microbiologically. Carbenicillin was unstable in all formulations containing, Acrosil, cetyl alcohol, cetostery| alcohol, Span 40, Span 80, white wax, and ‘wool alcohols. The activity was well retained in formulations ‘composed primarily of 10 10 20% liquid paraffin, 75 to 90% yellow soft paraffin, and 4 to 20% wool fat. Parabens and. ‘tocopheryl acetate had no effect onthe antibiotic activity. General Stability Considerations Carbidopa should be packaged in well-closed light-resstant containers and stored at controlled room temperature.* Pappert et al. reported that carbidopa is very unstable {in water with or without ascorbate present. Losses of about 30 and 60% occurred in eight and 24 hours, respectively, whether stored at 25°C, 12°C, or frozen. Exposure to light and the presence or absence of ascorbate did not change the rapid loss of carbidopa in aqueous solution,