Physicochemical Stability of Crystalline Sugars and Their Spray-Dried Forms: Dependence upon Relative Humidity and Suitability for Use in Powder Inhalers

Abstract

Lactose, trehalose, sucrose, and mannitol were purchased in crystalline form and fractionated by sieving. Coarse (125-212 µm) and fine (44-74 µm) free-flowing fractions were selected as typical of drug carriers in dry-powder inhalers. In addition, one batch of each sugar was spray-dried to form a respirable powder (> 50% [w/w], < 5 µm). Both fractions and the spray-dried powders were characterized before and after storage for 30 days at < 23%, 23%, 52%, 75% and 93% relative humidity (RH) at 25°C. Moisture uptake was determined by thermogravimetric analysis (TGA) validated by Karl Fischer titration. Sieve fractions (before storage at different RHs) and spray-dried materials (before and after storage) were further characterized by differential scanning calorimetry (DSC) and x-ray powder diffraction (XRPD). All crystalline sieve fractions (except sucrose at 93% RH) were stable at 25°C and showed insignificant moisture uptake when exposed to each relative humidity for 30 days. Sucrose dissolved in sorbed moisture at 93% RH. Spray-dried lactose, sucrose, and trehalose, which were collected in the amorphous form, showed moisture uptake, without recrystallization, when held for 30 days at 23% RH. These sugars recrystallized as sintered masses and became undispersible at ≥ 52% RH. Spray-dried mannitol was apparently 100% crystalline when collected directly from the spray-dryer; it did not show humidity-induced changes.

The physicochemical behavior of each sugar form is discussed as it relates to the sugar's suitability as a powder-inhaler excipient, with both conventional and protein drugs.     

Increased dissolution rates of tranilast solid dispersions extruded with inorganic excipients

The purpose of this study was to evaluate the performance of Neusilin® (NEU) a synthetic magnesium aluminometasilicate as an inorganic drug carrier co-processed with the hydrophilic surfactants Labrasol and Labrafil to develop Tranilast (TLT)-based solid dispersions using continuous melt extrusion (HME) processing. Twin-screw extrusion was optimized to develop various TLT/excipient/surfactant formulations followed by continuous capsule filling in the absence of any downstream equipment. Physicochemical characterization showed the existence of TLT in partially crystalline state in the porous network of inorganic NEU for all extruded formulations. Furthermore, in-line NIR studies revealed a possible intermolecular H-bonding formation between the drug and the carrier resulting in the increase of TLT dissolution rates. The capsules containing TLT-extruded solid dispersions showed enhanced dissolution rates and compared with the marketed Rizaben^® product.     

Investigation of Dissolution Enhancement of Itraconazole by Solid Dispersion in Superdisintegrants

Solid dispersions of itraconazole (ITR) in lactose, microcrystalline cellulose (MCC), and three superdisintegrants (Primogel, Kollidon CL, and Ac-Di-Sol) and their formulation into tablets were investigated with an objective of enhancing the dissolution rate of ITR from tablet formulations. X-ray diffraction (XRD) and differential scanning calorimetry (DSC) were used to characterize the dispersions. A marked enhancement in the dissolution rate of ITR was observed with all the excipients. The order for the excipients to enhance the dissolution rate was Ac-Di-Sol > Kollidon CL > Primogel > MCC > lactose. Solid dispersions in superdisintegrants gave much higher rates of dissolution than the dispersions in other excipients. Ac-Di-Sol gave the most improvement (28-fold) in the dissolution rate of ITR at a 1:1 drug: excipient ratio. Solid dispersions in superdisintegrants could be formulated into tablets. These tablets, apart from fulfilling all official and other specifications, exhibited higher rates of dissolution and dissolution efficiency (DE) values. XRD indicated the presence of ITR in amorphous form in the dispersions. DSC indicated a weak interaction between ITR and the excipients. Micronization and conversion of the drug into the amorphous form and the fast disintegrating and dispersing action of the superdisintegrants contribute to the enhancement of the dissolution rate of ITR from its solid dispersions in superdisintegrants and their corresponding tablet formulations.     

Determination of the crystallinity of cephalexin in pharmaceutical formulations by chemometrical near-infrared spectroscopy

Background: Near-infrared (NIR) spectroscopy has gained wide acceptance in the pharmaceutical industry as a rapid and non destructive method for drug identification and the determination of the drug content of preparations. Aim: The crystallinity of cephalexin (CEX) in microcrystalline cellulose (MCC) was determined using a nondestructive NIR reflectance spectroscopic technique. The molecular interaction of a ground amorphous solid of CEX was investigated by the method. Method: Six kinds of standard material with various degrees of crystallinity were prepared by the physical mixing of crystalline, amorphous CEX, and MCC. X-ray powder diffraction profiles and NIR spectra were recorded for standard samples. A chemometric analysis of the NIR spectral data sets was conducted using principal component regression (PCR). Results: The correlation between the actual crystallinity of CEX and that predicted using the conventional X-ray diffraction method showed a straight line with a slope of 1.000, an intercept of ?2.071 × 10^?5 and a correlation coefficient of determination (R²) of 0.974. The NIR spectrum of amorphous CEX showed significantly different peaks at 1176 and 1206 nm because of the CH₃ group from those of CEX. PCR was performed on various kinds of pretransformed NIR spectral data sets of standard samples of CEX. To minimize the SE of cross-validation (SECV), the spectral data sets were subjected to the leave-one-out method. The second derivative treatment in the range of 1176–1206 nm yielded the lowest SECV values. Based on a two-component model, a plot of the calibration data between the actual crystallinity of CEX and that predicted by the NIR method was obtained. The plot showed a straight line (Y = 0.995X + 0.117 and R² = 0.994; n = 18). The mean bias for the NIR and X-ray powder diffraction methods was calculated to be 1.52% and 2.26%, and mean accuracy was 3.06% and 7.14%, respectively. Conclusion: NIR spectral changes of crystalline CEX during grinding suggested that the intermolecular hydrogen bonds between the amino and carboxyl groups are destroyed and the binding of methyl groups is heightened by the resonance effect of carboxyl groups, and the crystals are transformed into amorphous CEX.     

Monoolein: A Review of the Pharmaceutical Applications

Earlies studies suggest that solution calorimetry can be used to determine the extent of amorphous content of drug and excipient, when the solubility and dissolution rate of the compound in the chosen solvent are reasonably high. In the present study, the use of solution calorimetry for assessment of amorphous content of a sample that is not completely dissolved in a solvent was evaluated. Physical mixtures of lactose and spray‐dried lactose samples were analysed. The amorphous content of the physical mixtures and the spray‐dried samples varied from 0% to 100% determined by isothermal microcalorimetry. The enthalpy of solution (Δ_solH) was determined in water. The lactose samples were dissolved quickly in water. In addition, the enthalpy accompanied with an addition of a lactose sample in an over saturated aqueous solution (Δ_satH) (prepared from the corresponding lactose sample) was determined. The lactose sample did not completely dissolve in the over saturated aqueous solution. An excellent correlation was observed between Δ_solH and the amorphous content of the samples. Interestingly, there was a linear correlation also between Δ_satH and the amorphous content of the samples. Further, a linear relationship was observed between the Δ_satH and the Δ_solH of the samples. Therefore, solution calorimetry may represent a rapid and simple method for determining the amorphous content also in samples that are not completely dissolved in the solvent.     

Modification of α-lactose monohydrate as a direct compression excipient using roller compaction

Abstract

Roller compaction was used to prepare a direct-compressed lactose excipient using crystalline α-lactose monohydrate. The effect of various roller compaction process parameters (compaction pressure, compaction repetition, and speed ratio) on the characteristics of compacted α-lactose monohydrate was investigated. Results were compared with data obtained using industrial spray-dried lactose and lactose samples with different degrees of crystallinity. XRPD analysis revealed that roller compaction reduced the crystallinity of α-lactose monohydrate, and the resulting material is similar to spray-dried lactose in behavior as a direct compression excipient. Roller compaction introduced desirable characteristics to the raw α-lactose monohydrate by inducing changes in crystallinity and particle morphology. Scanning electron microscopy results indicated that the compaction process converted some of the original torpedo-shaped crystals of α-lactose monohydrate into a more cylindrical shape with rounded edges. Compaction pressure and repetition of compaction have a significant effect on the modification of the crystallinity of the processed, raw α-lactose monohydrate.     

Evaluation of Anhydrous α-Lactose,A New Excipient in Direct Compression

Abstract

Different forms of lactose are available for direct compression of tablets. The use of spray-dried lactose, which has good flow and compressibility characteristics, is limited by its stability when stored under humid conditions. Sieved crystalline fractions of α-lactose monohydrate such as the 100 mesh fraction, have very good flow properties and an outstanding stability, but the compressibility is so poor, that it can be used only in combination with other filler-binders, like microcrystalline cellulose. A third form of lactose, increasingly used in direct compression is anhydrous lactose. The commercially available products generally consist of an excess of β next to α-lactose. They both have good binding and stability characteristics, but a flowability which is less than optimum. The latter is caused by the rather irregular particle shape and the relatively high amount of fines. A newly developed form of lactose is anhydrous α-lactose. It is prepared by dehydration of α-lactose monohydrate. Binding, flow and stability properties of this excipient were compared with the properties of other filler/binders. The results show that the compressibility of anhydrous α-lactose was about the same as that of anhydrous β-lactose.

The flow properties of anhydrous α-lactose were even better than the very good fluidity of α-lactose monohydrate 100 mesh. At storage under normal or humid conditions, there was no change in hardness of tablets compressed from anhydrous α-lactose.

A comparative evaluation of the effect of mixing with magnesium stearate on the binding properties of filler/binders showed that all the lactose products investigated, including anhydrous α-lactose, behave in an intermediate manner, between complete plastic deformation and complete brittle fracture. For this reason there is a limited decrease in crushing strength for tablets compressed from anhydrous α-lactose, during mixing with magnesium stearate.

Some formulation examples will show that anhydrous α-lactose is a very useful filler/binder in direct compression, of which tablets with a low weight variation, sufficient strength, a low friability, a fast disintegration and a high drug release can be prepared.     

Selection of excipient,solvent and packaging to optimize the performance of spray-dried formulations: case example fenofibrate

Context: Along with other options, solid dispersions prepared by spray drying offer the possibility of formulating poorly soluble drugs in a rapidly dissolving format. As a wide range of potential excipients and solvents is available for spray drying, it is usually necessary to carry out a comprehensive array of studies to arrive at an optimal formulation.

Objective: To study the influence of formulation parameters such as co-sprayed excipients, solvents and packaging on the manufacture, in vitro performance and stability of spray-dried oral drug products using fenofibrate as a model drug.

Materials and methods: Solid dispersions of fenofibrate with different amorphous polymers were manufactured from two solvent systems by spray drying. These were characterized in terms of physicochemical properties, crystalline content and dissolution behavior in biorelevant media upon production and after storage in two packaging systems (Glass and Activ-Vials^?).

Results and discussion: Spray drying the same formulation from two different solvents led to different physicochemical properties, dissolution behavior and long-term stability. The dissolution behavior and long-term stability also varied significantly among excipients. The viscosity of the polymer and the packaging material proved to be important to the long-term stability.

Conclusion: For spray-dried products containing fenofibrate, the excipients were ranked according to dissolution and stability performance as follows: PVP derivatives >> HPMC 2910/15, HPMCAS-MF, HP-β-CD >> PVP:PVA 2:8. EtOH 96% proved superior to acetone/water for spray drying with polymers. The results were used to propose a general approach to developing spray-dried formulations of poorly soluble drugs.     

The Use of Organic Vapor Sorption to Determine Low Levels of Amorphous Content in Processed Pharmaceutical Powders

ABSTRACT

Organic dynamic vapor sorption (organic-DVS) was used to characterize amorphous content in known amorphous-crystalline mixtures of lactose and salbutamol sulfate. N-octane was chosen as an apolar probe and measurements were carried out by exposing mixtures of each sample to partial pressures 0–90% p/p₀. A linear relationship between amorphous content and n-octane partial pressure was observed for both lactose and salbutamol sulfate with R² values of 0.992 and 0.999, respectively. In addition, the influence of sequential mechanical processing in a ball mill on the amorphous content in crystalline lactose was investigated. Cumulative milling times resulted in an exponential increase in amorphous content (using the linear relationship obtained for lactose), with a maximum amorphous content of 14% being induced after 60 min milling. In comparison, analysis of the 60 min mill time samples after exposure to 85% relative humidity suggested 0.00% amorphous content.     

Monitoring of the manufacturing process for ambroxol hydrochloride tablet using NIR-chemometric methods: compression effect on content uniformity model and relevant process parameters testing

This study aimed at using near-infrared (NIR) spectroscopy to monitor compaction pressure for simultaneously determining the tensile strength and content uniformity, as well as moisture and mean particle size of ambroxol hydrochloride tablets. The content uniformity, compression force and tensile strength of the laboratory samples were obtained by pressing a mixture of active principle and excipient components into tablets. To reduce the spectral baseline shift of the laboratory samples, the compaction pressure applied to the mixture was assessed by a variable pressure test. Production samples were added to the test and subjected to principal component analysis. The expanded partial least-squares (PLS) calibration model used to quantify the active content was more accurate than the model constructed from laboratory samples using the production tablets included in the calibration set. The model showed good predictability, with correlation coefficient (R) 0.9977. The validation and reliability of the content model were evaluated to determine trueness and reliability for the measurement of individual production tablets and the laboratory tablets with drug content ranging from 24 to 36?mg. The PLS calibration models for compression force and tensile strength were constructed using the same spectral set assuming both were highly related. These models yielded high R values (0.9955 and 0.9910). The R values of the moisture and mean particle size were 0.9994 and 0.9919, respectively. This study demonstrated that NIR spectroscopy combined with chemometric techniques can be successfully used to quantitatively monitor the tablet manufacturing process in the pharmaceutical industry.     

Investigation of dissolution enhancement of itraconazole by solid dispersion in superdisintegrants

Solid dispersions of itraconazole (ITR) in lactose, microcrystalline cellulose (MCC), and three superdisintegrants (Primogel, Kollidon CL, and Ac-Di-Sol) and their formulation into tablets were investigated with an objective of enhancing the dissolution rate of ITR from tablet formulations. X-ray diffraction (XRD) and differential scanning calorimetry (DSC) were used to characterize the dispersions. A marked enhancement in the dissolution rate of ITR was observed with all the excipients. The order for the excipients to enhance the dissolution rate was Ac-Di-Sol > Kollidon CL > Primogel > MCC > lactose. Solid dispersions in superdisintegrants gave much higher rates of dissolution than the dispersions in other excipients. Ac-Di-Sol gave the most improvement (28-fold) in the dissolution rate of ITR at a 1:1 drug:excipient ratio. Solid dispersions in superdisintegrants could be formulated into tablets. These tablets, apart from fulfilling all official and other specifications, exhibited higher rates of dissolution and dissolution efficiency (DE) values. XRD indicated the presence of ITR in amorphous form in the dispersions. DSC indicated a weak interaction between ITR and the excipients. Micronization and conversion of the drug into the amorphous form and the fast disintegrating and dispersing action of the superdisintegrants contribute to the enhancement of the dissolution rate of ITR from its solid dispersions in superdisintegrants and their corresponding tablet formulations.     

Tabletability of Maltodextrins and Acetaminophen Mixtures

Abstract

Tabletability of five types of maltodextrin, a filler/binder excipient, was studied by testing their loading potentials with acetaminophen. The formulations consisted of excipient and acetaminophen at five different ratios and magnesium stearate at a 0.5% concentration. These mixtures were compacted employing an Integrated Compaction Research System at a constant punch velocity of 100 mm/sec. under varying applied pressures from 50 to 450 MPa. Compaction data were evaluated using the total work of compaction vs applied pressure plots whilst the post-compaction tests included the measurements of crushing force, disintegration time, and friability of the resulting tablets. Both the energy involved during the compaction of a formulation and the crushing force values of the resulting tablets decreased as the amount of the maltodextrin in a formulation was reduced. Maltodextrins exhibited adequate binding potential at acetaminophen drug loading levels of only up to twenty-five percent. The disintegration times of the tablets containing maltodextrins were generally prolonged and this was found to be due to the formation of a “gel” layer around the tablet which formed on immersion into water. The tabletability of maltodextrins were also compared to that of Fast-Flo lactose, and the compactability of these excipients were found to be similar.     

Formulation and Release Kinetics of Sustained Release Phenylpropanolamine Hydrochloride Granules and Tablets

Abstract

Sustained release phenylpropanolamine hydrochloride (PPH) granules and tablets were prepared using HPMC, HPMC and SCMC, Eudragit RS, Eudragit RS+L or HPMC + Eudragit RS matrices. The release pattern of PPH from the prepared granules and tablets was found to be in the following order HPMC > HPMC + SCMC > RS > RS + 1> HPMC + RS. The results revealed that, although the drug concentration was kept constant in all the prepared granules and tablets, the drug release from these formulations was clearly different and depends mainly on the type of matrix used. The presence of Eudragit L with Eudragit RS and Eudragit RS with HPMC resulted in a marked decrease in the drug release compared with that obtained from the matrix containing HPMC or Eudragit RS alone. The release data of PPH from the prepared granules and tablets were treated mathematically according to zero order, first order, Langenbuchar, modified Langenbucher and Higuchi models. The results revealed that no one model was able adequately to describe the drug release profiles from these formulations. In-vivo studies in human volunteers showed that, the peak urinary excretion of PPH occurred over a sustained period from 2 to 6.5 hr in case of HPMC + SCMC tablets and from 2 to 10 hr in case of either RS+L or HPMC + RS tablets.     

Determination of amorphous content of lactose samples by solution calorimetry

Earlies studies suggest that solution calorimetry can be used to determine the extent of amorphous content of drug and excipient, when the solubility and dissolution rate of the compound in the chosen solvent are reasonably high. In the present study, the use of solution calorimetry for assessment of amorphous content of a sample that is not completely dissolved in a solvent was evaluated. Physical mixtures of lactose and spray-dried lactose samples were analysed. The amorphous content of the physical mixtures and the spray-dried samples varied from 0% to 100% determined by isothermal microcalorimetry. The enthalpy of solution (Δ_solH) was determined in water. The lactose samples were dissolved quickly in water. In addition, the enthalpy accompanied with an addition of a lactose sample in an over saturated aqueous solution (Δ_satH) (prepared from the corresponding lactose sample) was determined. The lactose sample did not completely dissolve in the over saturated aqueous solution. An excellent correlation was observed between Δ_solH and the amorphous content of the samples. Interestingly, there was a linear correlation also between Δ_satH and the amorphous content of the samples. Further, a linear relationship was observed between the Δ_satH and the Δ_solH of the samples. Therefore, solution calorimetry may represent a rapid and simple method for determining the amorphous content also in samples that are not completely dissolved in the solvent.     

Studies of Hie Effect of Powder Moisture Content on Drug Release from Hard Gelatin Capsules

The in vitro dissolution of model formulations from hard gelatin capsules containing drug: diluent powder mixtures at different moisture levels has been studied. The capsules were filled to a constant porosity of 50%. to contain either sodium barbitone or barbitone in 50:50 mixture with lactose or maize starch, the latter at one of three moisture levels. In addition, capsules containing drug alone were examined. The wettability and polarity indeces of the individual powders and binary mixtures, as well as the permeability and liquid penetration rates of powder beds were also determined.

The presence of either excipient was found to modify the time for 50% drug dissolution (t₅₀) compared with drug alone for all formulations examined, apart from the sodium barbitone: lactose capsules. The rate of drug dissolution was also dependent on the initial powder moisture content for the drug:starch formulations. Open storage of capsules at 20^%/75%. R.lt. generally increased t₅₀figures.

The findings are discussed in terms of the nature of the surfaces of the powder particles, moisture sorption phenomena and factors such as powder bed permeability and water penetitration lates.     

Development of fast-dissolving tablets of flurbiprofen-cyclodextrin complexes

The present study was aimed at developing a tablet formulation based on an effective flurbiprofen-cyclodextrin system, able to allow a rapid and complete dissolution of this practically insoluble drug. Three different cyclodextrins were evaluated: the parent β-cyclodextrin (previously found to be the best partner for the drug among the natural cyclodextrins), and two amorphous, highly soluble β-cyclodextrin derivatives, i.e., methyl-β-cyclodextrin and hydroxyethyl-β-cyclodextrin. Equimolar drug-cyclodextrin binary systems prepared according to five different techniques (physical mixing, kneading, sealed-heating, coevaporation, and colyophilization) were characterized by Differential Scanning Calorimetry, x-ray powder diffractometry, infrared spectroscopy, and optical microscopy and evaluated for solubility and dissolution rate properties. The drug solubility improvement obtained by the different binary systems varied from a minimum of 2.5 times up to a maximum of 120 times, depending on both the cyclodextrin type and the system preparation method. Selected binary systems were used for preparation of direct compression tablets with reduced drug dosage (50 mg). Chitosan and spray-dried lactose, alone or in mixture, were used as excipients. All formulations containing drug-cyclodextrin systems gave a higher drug dissolved amount than the corresponding ones with drug alone (also at a dose of 100 mg); however, the drug dissolution behavior was strongly influenced by formulation factors. For example, for the same drug-cyclodextrin product the time to dissolve 50% drug varied from less than 5 minutes to more than 60 minutes, depending on the excipient used for tableting. In particular, only tablets containing the drug kneaded with methyl-β-cyclodextrin or colyophilized with β-cyclodextrin and spray-dried lactose as the only excipient satisfied the requirements of the Food and Drug Administration (FDA) for rapid dissolving tablets, allowing more than 85% drug to be dissolved within 30 minutes. Finally, it can be reasonably expected that the obtained drug dissolution rate improvement will result in an increase of its bioavailability, with the possibility of reducing drug dosage and side effects.     

Screening pharmaceutical excipient powders for use in commercial 3D binder jetting printers

Binder jetting is an additive manufacturing technique that creates three-dimensional constructs from a powder feedstock. It is used by several industries, including pharmaceuticals. This additive approach to manufacture provides several functional benefits that are not easily achievable using conventional manufacturing methods. There is currently only limited publicly available knowledge that details the requirements of an effective binder jetting powder. Specifically in the pharmaceutical industry, since the 2015 release of Spritam®, a binder-jetted tablet containing levetiracetam, no new pharmaceutical tablets have been produced using such methods.There appears to be gap in powder technology expertise and the development of 3D printing processes. Our goal is to enhance our knowledge in terms of powder flow, powder wetting and powder binding to link particles with process and build the capability to create a greater range of powders suitable to be binder-jetted into new products. After initially screening several standard pharmaceutical excipient powders for their relevant properties, two candidates showed best fit potential for use in binder jetting, specifically microcrystalline cellulose (Pharmacel 101 and 102) and lactose (Lactohale 200). Using simple formulations of these pharmaceutical excipient powders as a model, we analysed for printability and powder performance using a range of quantitative parameters including dimensional accuracy, construct hardness, friability, porosity and surface finish. In general, formulations of these powders showed good printability, but some powder blends produced constructs with more obvious manufacturing imperfections. Several routes to improve the printability of these pharmaceutical powders are proposed for future works. Ultimately, this work provides a fundamental basis to start to quantitatively assess the potential of standard pharmaceutical excipient powders in binder jetting printers using powder characterisation techniques and print quality outcomes.     

Novel nano-cellulose excipient for generating non-Newtonian droplets for targeted nasal drug delivery

Purpose: Thickening polymers have been used as excipients in nasal formulations to avoid nasal run-off (nasal drip) post-administration. However, increasing the viscosity of the formulation can have a negative impact on the quality of the aerosols generated. Therefore, the study aims to investigate the use of a novel smart nano-cellulose excipient to generate suitable droplets for nasal drug delivery that simultaneously has only marginally increased viscosity while still reducing nasal drips.

Methods: Nasal sprays containing nano-cellulose at different concentrations were investigated for the additive’s potential as an excipient. The formulations were characterized for their rheological and aerosol properties. This was then compared to conventional nasal spray formulation containing the single-component hydroxyl-propyl methyl cellulose (HPMC) viscosity enhancing excipient.

Results: The HPMC-containing nasal formulations behave in a Newtonian manner while the nano-cellulose formulations have a yield stress and shear-thinning properties. At higher excipient concentrations and shear rates, the nano-cellulose solutions have significantly lower viscosities compared to the HPMC solution, resulting in improved droplet formation when actuated through conventional nasal spray.

Conclusions: Nano-cellulose materials could potentially be used as a suitable excipient for nasal drug delivery, producing consistent aerosol droplet size, and enhanced residence time within the nasal cavity with reduced run-offs compared to conventional polymer thickeners.     

Development of a Lyophilized Formulation for (R,R)-Formoterol (L)-Tartrate

(R,R)-formoterol is a β-agonist for inhalation. Aqueous instability suggested the need for a reconstitutable lyophilized dosage form. The objective of these studies was to devise a stable, rapid-dissolving, therapeutically compatible dosage form. The effects of diluents and residual moisture on the stability of thermally stressed formoterol formulations were investigated. Drug and various excipients (acetate, lactose, and mannitol) were lyophilized and placed in humidity chambers (0 to 90% relative humidity) at 25 to 50°C. Stability was characterized by time-dependent changes using HPLC, pH, and XRD. Residual moistures were determined by Karl Fisher methods. Regression models were developed to quantify the effects of formulation and environmental variation on drug stability. Solid-state instability was observed as a function of high residual moisture and diluent type. Although the residual moistures in mannitol formulations were typically below 1%, the degradation rate (50°C) varied from 2 to 10 mcg/day, which was 1.3- to 20-fold high than observed for lactose formulations under the same relative humidity conditions. At high relative humidity, the presence of acetate significantly increased the degradation rate (p < 0.04). The critical residual moisture content for lactose formulations was 3%. The amount of lactose was optimized by evaluating the degradation over the temperature range 25 to 50°C. Mannitol and acetate were shown to be unsuitable excipients, and an optimal lactose amount was 50 mg for vials containing 50 mcg of drug.