Development and evaluation of dexibuprofen formulation with fast onset and prolonged effect

In the present study, in order to improve the solubility and bioavailability of poorly water-soluble dexibuprofen, a novel dexibuprofen-loaded solid dispersion was developed using the spray-drying technique. The controlled-release dexibuprofen formulation was developed by combining the immediate-release dispersion powder and the sustained-release formula. The solid dispersion composed of dexibuprofen/poloxamer 407/hydroxypropyl methylcellulose (HPMC) 2910 (50?cps)/sodium lauryl sulfate (SLS) (10/1/4/0.1?mg) was selected as the immediate-release formulation due to its increased solubility and dissolution rate. This immediate-release formulation showed a significantly higher initial plasma concentration, AUC, and C_max of dexibuprofen than those of dexibuprofen powder. Based on the prolonged effect of high plasma concentration, the formulation consisting of dexibuprofen/ethylcellulose/HPMC 2910 (4000?cps)/magnesium stearate (66/16.5/16.5/1?mg) was selected as the sustained-release formulation. Finally, the controlled-release (CR) formulation was prepared by encapsulating the immediate-release and sustained-release formulations in hard gelatin capsules. The proposed CR formulation showed enhanced AUC (5.5-fold) and C_max (3.5-fold) compared to dexibuprofen powder. The results of the present study suggest that the CR formulation containing dexibuprofen may be a potential oral dosage form for a fast onset and a prolonged effect of poorly water-soluble dexibuprofen.     

Understanding stability relationships among three curcumin polymorphs

Understanding thermodynamic stability relationship among polymorphs of any active pharmaceutical ingredient (API) is a necessary step for drug formulation development. Knowledge of such relationship enables identification of a stable polymorphic form at the prevalent conditions. Curcumin, a pharmaceutically active ingredient found in herbal spice turmeric, exists in three polymorphic forms; a monoclinic form (Form 1) and two orthorhombic forms (Form 2 and Form 3). However, thermodynamic stability relationships among curcumin polymorphs have not been ascertained yet. This work therefore, was focused on understanding thermodynamic stability relationships among curcumin polymorphs. During purification of curcumin, the pressure applied for vacuum evaporation of organic solvent was found to significantly affect the polymorphic outcome. Form 1 was obtained at pressures ranging from 300 to 400?mbar whereas Form 2 was obtained at pressures ranging from 100 to 200?mbar. Form 3 was obtained by liquid antisolvent precipitation using ultrasound and Bovine Serum Albumin (BSA) as an additive. The obtained polymorphs were characterized by X-ray diffraction (XRD) and Differential Scanning Calorimetry (DSC) techniques. Relative stability of polymorphs was established by conducting solvent mediated transformation studies, thermal analysis through DSC and variable temperature X-ray diffraction studies (VT-XRD). It was observed that Form 2 and Form 3 irreversibly convert to Form 1 upon heating. Further, Form 2 and Form 3 convert to Form 1 in aqueous organic solutions at temperatures ranging from 0?°C to 50?°C. Thus, the curcumin polymorphs were found to be monotropically related to each other with the monoclinic form (Form 1) being the most stable form.     

Early development evaluation of AZD8081: a substrate for the NK receptors

The purpose of the present study was to find out if AZD8081, a dual neurokinin (NK)1/2 receptor antagonist, was suitable for development of an oral, solid immediate release (IR) formulation and in a further perspective also as an oral extended release (ER) formulation. AZD8081 is a base with pK(a) values <2.5 and about 8.5. The measured intrinsic solubility is about 0.1?mg/mL and the solubility in FaSSIF (fasted simulated small intestinal fluid) is about 3.2?mg/mL. Aqueous buffer solutions are stable for at least 1 month between pH 1-7 up to 37°C. In the solid-state, a mixture of amorphous and crystalline substance showed significant chemical instability in the initial stress testing studies. No degradation was, however, observed for highly crystalline material at similar conditions. It is concluded that the impurity profile and/or the present solid-state of the batches affect the stability of the substance. The amorphous contribution of the substance is the main cause to the observed degradation in solid-state. Crystalline AZD8081 is polymorphic with two known monotropic forms, form A and form B. Both forms are only slightly hygroscopic ansolvates with melting points of approximately 108°C and 117°C, respectively. Form B is the more stable of the two forms and is therefore most suited for further development. The candidate is suitable for development of standard IR formulations since no specific limitations of significance for formulation development were identified. In addition, the good stability in human intestinal fluid and in colon slurry makes AZD8081 a suitable candidate for ER formulation.     

X-Ray Powder Diffraction Study on the Grinding Effect of the Polymorphs of a Novel and Orally Effective Uricosuric Agent: FR76505

The polymorphism of a novel and orally effective uricosuric agent, [3-(4-bromo-2-fluorobenzyl)-7-fluoro-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-1-yl] acetic acid, designated as FR76505, was characterized by X-ray powder diffractometry and thermal analysis. In the crystalline state, FR76505 exists in at least three polymorphic forms, Forms A, B and C. Among them, Form B is a stable form, and Forms A and C which are transformed to Form B are metastable forms. Form C was not stable enough to keep its state even at room temperature. Therefore, it was not suitable to be used for the pharmaceutical preparation, and further investigation for Form C was not carried out. The mechanochemical effect of grinding makes the crystallite size smaller and the lattice strain larger for both the Forms A and B crystals. After grinding for 60 minutes, both forms changed into noncrystalline powders. Thermal behavior of the ground sample was investigated by the X-ray powder diffractometry under the heating condition, as well as the thermal analysis. It is concluded that the mechanochemical effect of grinding made Form A change into Form B easily, and the increase of a grinding time led the transformation temperature lower.     

X-Ray Powder Diffraction Study on the Grinding Effect of the Polymorphs of a Novel and Orally Effective Uricosuric Agent: FR76505

The polymorphism of a novel and orally effective uricosuric agent, [3-(4-bromo-2-fluorobenzyl)-7-fluoro-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-1-yl] acetic acid, designated as FR76505, was characterized by X-ray powder diffractometry and thermal analysis. In the crystalline state, FR76505 exists in at least three polymorphic forms, Forms A, B and C. Among them, Form B is a stable form, and Forms A and C which are transformed to Form B are metastable forms. Form C was not stable enough to keep its state even at room temperature. Therefore, it was not suitable to be used for the pharmaceutical preparation, and further investigation for Form C was not carried out. The mechanochemical effect of grinding makes the crystallite size smaller and the lattice strain larger for both the Forms A and B crystals. After grinding for 60 minutes, both forms changed into noncrystalline powders. Thermal behavior of the ground sample was investigated by the X-ray powder diffractometry under the heating condition, as well as the thermal analysis. It is concluded that the mechanochemical effect of grinding made Form A change into Form B easily, and the increase of a grinding time led the transformation temperature lower.     

Influence of capsule shell composition on the performance indicators of hypromellose capsule in comparison to hard gelatin capsules

The purpose of this study was to assess the in vitro performances of “vegetable” capsules in comparison to hard gelatin capsules in terms of shell weight variation, reaction to different humidity conditions, resistance to stress in the absence of moisture, powder leakage, disintegration and dissolution. Two types of capsules made of HPMC produced with (Capsule 2) or without (Capsule 3) a gelling agent and hard gelatin capsules (Capsule 1) were assessed. Shell weight variability was relatively low for all tested capsules shells. Although Capsule 1 had the highest moisture content under different humidity conditions, all capsule types were unable to protect the encapsulated hygroscopic polyvinylpyrrolidone (PVP) powder from surrounding humidity. The initial disintegration for all Capsule 1 occurred within 3?min, but for other types of capsules within 6?min (n?=?18). Dissolution of acetaminophen was better when the deionized water (DIW) temperature increased from 32 to 42?°C in case of Capsule 1, but the effect of temperature was not significant for the other types of capsules. Acetaminphen dissolution from Capsule 1 was the fastest (i.e. >90% in 10?min) and independent of the media pH or contents unlike Capsule 2 which was influenced by the pH and dissolution medium contents. It is feasible to use hypromellose capsules shells with or without gelling agent for new lines of pharmaceutical products, however, there is a window for capsule shells manufacturing companies to improve the dissolution of their hypromellose capsules to match the conventional gelatin capsule shells and eventually replace them.     

Early development evaluation of AZD8081: a substrate for the NK receptors

The purpose of the present study was to find out if AZD8081, a dual neurokinin (NK)1/2 receptor antagonist, was suitable for development of an oral, solid immediate release (IR) formulation and in a further perspective also as an oral extended release (ER) formulation. AZD8081 is a base with pK_a values <2.5 and about 8.5. The measured intrinsic solubility is about 0.1?mg/mL and the solubility in FaSSIF (fasted simulated small intestinal fluid) is about 3.2?mg/mL. Aqueous buffer solutions are stable for at least 1 month between pH 1–7 up to 37°C. In the solid-state, a mixture of amorphous and crystalline substance showed significant chemical instability in the initial stress testing studies. No degradation was, however, observed for highly crystalline material at similar conditions. It is concluded that the impurity profile and/or the present solid-state of the batches affect the stability of the substance. The amorphous contribution of the substance is the main cause to the observed degradation in solid-state. Crystalline AZD8081 is polymorphic with two known monotropic forms, form A and form B. Both forms are only slightly hygroscopic ansolvates with melting points of approximately 108°C and 117°C, respectively. Form B is the more stable of the two forms and is therefore most suited for further development. The candidate is suitable for development of standard IR formulations since no specific limitations of significance for formulation development were identified. In addition, the good stability in human intestinal fluid and in colon slurry makes AZD8081 a suitable candidate for ER formulation.     

New metastable form of glibenclamide prepared by redispersion from ternary solid dispersions containing polyvinylpyrrolidone-K30 and sodium lauryl sulfate

Modification of polymorphic forms of poorly water-soluble drugs is one way to achieve the desirable properties. In this study, glibenclamide (GBM) particles with different polymorphic forms, including a new metastable form, were obtained from redispersion of ternary solid dispersion systems. The ternary solid dispersion systems, consisting of GBM, polyvinylpyrrolidone-K30 (PVP-K30) and sodium lauryl sulfate (SLS), were prepared by solvent evaporation method and subsequently redispersed in deionized water. The precipitated drug particles were then collected at a given time period. The drug particles with different polymorphic forms could be achieved depending on the polymer/surfactant ratio. Amorphous drug nanoparticles could be obtained by using a high polymer/surfactant ratio, whereas two different crystalline forms were obtained from the systems containing low polymer/surfactant ratios. Interestingly, a new metastable form IV of GBM with improved dissolution behavior could be obtained from the system of GBM:PVP-K30:SLS with the weight ratio of 2:2:4. This new polymorphic form IV of GBM was confirmed by differential scanning calorimetry (DSC), Fourier transform infrared (FT-IR) spectroscopy, powder X-ray diffractometry (PXRD) and solid state ¹³C nuclear magnetic resonance (NMR) spectroscopy. The molecular arrangement of the new polymorphic form IV of GBM was proposed. The GBM particles with polymorphic form IV also showed an improved dissolution behavior. In addition, it was found that the formation of the new polymorphic form IV of GBM by this process was reproducible.     

Development of a HPMC-based controlled release formulation with hot melt extrusion (HME)

The objective of this study was to develop hydroxypropyl methylcellulose (HPMC) based controlled release (CR) formulations via hot melt extrusion (HME) with a highly soluble crystalline active pharmaceutical ingredient (API) embedded In the polymer phase. HPMC is considered a challenging CR polymer for extrusion due to its high glass transition temperature (T_g), low degradation temperature, and high viscosity. These problems were partially overcome by plasticizing the HPMC with up to 40% propylene glycol (PG). Theophylline was selected as the model API. By using differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA), dynamic mechanical analysis (DMA), and X-ray powder diffraction (XRPD), the physical properties of the formulations were systematically characterized. Five grades of HPMC (Methocel^®) – E6, K100LV, K4M, K15M, and K100M – were tested. The extrusion trials were conducted on a 16?mm twIn screw extruder with HPMC/PG placebo and formulations containing theophylline/HPMC/PG (30:42:28, w/w/w). The dissolution results showed sustained release profiles without burst release for the HPMC K4M, K15M, and K100M formulations. The extrudates have good dissolution stability after being stressed for 2 weeks under 40°C/75% RH open dish conditions and the crystalline API form did not change upon storage. Overall, the processing windows were established for the HPMC based HME-CR formulations.     

Preparation and pharmacokinetics in beagle dogs of once-a-day tetramethylpyrazine phosphate sustained-release pellets

In this study, once-a-day tetramethylpyrazine phosphate (TMPP) sustained-release pellets were successfully prepared. The pellets cores were carried out in extrusion-spheronization machine and then coated in fluidized-bed. To optimize cumulative release profile, two different coating systems with the same the TMPP pellets cores were employed. The first coating system consisted of surlease, containing HPMC E5 (0.1% w/w), i.e., P1. The second coating system only consisted of surlease, i.e., P2. The two kinds of coating systems were both given coating levels in terms of weight gain of 10%. The resulted once-a-day TMPP sustained-release pellets (OTSP), the mixture of P1 and P2 with the weight proportion of 1:1, were filled in a capsule (150?mg TMPP/capsule). The relative bioavailability of OTSP was studied in six beagle dogs after oral administration using a commercial TMPP tablets as a reference. The C(max) and T(max) for OTSP and TMPP tablets were 213.06?ng/mL, 2.50?h and 3402.13?ng/mL, 0.33?h, respectively and the relative bioavailability of P3 was 97.18% compared with TMPP tablets. Based on the results, it was indicated that TMPP sustained-release pellets and TMPP conventional tablets were bioequivalent.     

Some observations on the liquid crystalline and gel behaviors of aqueous dispersions of a prodrug

BMS-830216 is a diprotic acid prodrug of two pK_a values (<2 and 6.8) with high apparent solubility at pH ≥ 7. At?～?pH 4 solutions of BMS-830216 appear to be surface active, in which their surface tension can be reduced from 72 to 65 dynes when its concentrations is above the critical aggregation concentration (CAC～0.2?mM). Additionally, at this pH, BMS-830216 tends to form liquid crystalline phases (at ≥ 2?mg/mL) in acetate buffer when using tris salt. Furthermore, after raising the concentration beyond 20?mg/g, formation of gel-like dispersions was noted. These gel-like dispersions exhibited a strong elastic strength, significantly impacting the dissolution behavior of the tris salt. Mechanistically, it is likely that BMS-830216 tris salt in solution first forms a lamellar phase followed by formation of a gel phase at higher concentrations (≥20?mg/mL). As indicated by SAXS, the lamellar phase formed seems to have two d-spacing values (～5?nm and ～10?nm (weak), which seems to correspond to two molecules connected tail by tail (5?nm). Further investigation is needed for phase identification, as their properties can affect the physical behavior of BMS-830216 in the development of pharmaceutical dosage forms.     

Water soluble cellulose acetate: a versatile polymer for film coating

The objective of this study was to investigate the use of water soluble cellulose acetate (WSCA) as a film coating material for tablets. Aspirin (ASA) tablets were prepared by direct compression and coated with either WSCA or HPMC (hydroxypropyl methylcellulose) dispersions. Coatings of 1-3%, depending on the intended application, were applied to the model drug (ASA) tablets employing a side-vented coating pan. Free films of WSCA, prepared by cast method, are crystal clear and, depending on the viscosity grade, are flexible, strong and durable. WSCA has the capability of forming free films without plasticizers and the films dry at room temperature. Glass transition temperature, Tg, was determined by differential scanning calorimetry. The Tg of WSCA is significantly higher relative to HPMC. Inclusion of plasticizer lowers the Tg of WSCA and effective plasticizers were PEG 400 and glycerin. Low viscosity WSCA was more soluble in water (25-30%) relative to medium viscosity WSCA (10-15%). WSCA solutions exhibited no increase in viscosity with an increase in temperature. Samples of coated (WSCA and HPMC) tablets and uncoated ASA cores were packaged for stability studies at room and elevated temperature storage. Physical stability of ASA tablets coated with 2:1 LV: MV (low viscosity: medium viscosity) WSCA formulations was better when compared to tablets coated with HPMC. Dissolution stability of WSCA coated ASA was similar to the physical stability results. After three months at elevated temperature (35 and 45°C), the WSCA coated tablets complied with USP dissolution requirements for ASA, while the HPMC coated tablets did not. There was no difference in moisture (weight) gain of ASA tablets coated with either WSCA or HPMC. The WSCA coated tablets were not sticky or tacky, while the HPMC coated tablets were tacky and stuck together.     

Polymorphism of Fostedil: Chracterization and Polymophic Change by Mechanical Treatments

Abstract

Two crystal forms of fostedil were characterized using X-ray diffraction patterns and infrared spectra. The melting points of polymorph I and II were 95.3 °C and 96.4 °C, respectively.

Solubility studies demonstrated that, of the two fostedil polymorphs, form II was slightly more soluble than form I. The free energy difference between two polymorphs was small (71.8 cal/mol at 37 °C). Both crystals melted at about 60 °C in water considerably below the melting points.

Compression of form II at a compression force of 500 - 1000 kg/cm² induced polymorphic changes in the crystal. Similar changes also were produced through grinding. The effects of some diluents on the polymorphic transformation from form II into form I by grinding were also studied. Microcrystalline cellulose and corn starch showed a polymorphic transfomation-accelerating effects.

Form I is more suitable for the pharmaceutical preparation.     

Polymorphic transformation of anhydrous caffeine under compression and grinding: a re-evaluation

Polymorphic transformations that may occur during mechanical treatment are of great interest for the production of pharmaceutical solids. Anhydrous caffeine is a well-known example of such transformations but a careful reading of the already existing literature shows that published results are contradictory. In this study, both forms of caffeine, form I and form II, respectively metastable and stable at ambient pressure and temperature, were submitted to compression in an instrumented alternative press and to grinding, and were studied before and after treatment by X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC). Compression experiments showed no changes of form II during compression, whereas form I was partially transformed into form II. Nevertheless, this transformation did not happen immediately. Form II appeared after a kinetically slow transformation and was clearly detectable only after a few days, fact that was never mentioned by previous authors. Same phenomenon was observed after the grinding of form I but also after an extensive grinding of form II. DSC and XRPD measurements indicated that polymorphic transformation did not happen directly, but that a new intermediate form was obtained after mechanical treatment, which slowly turned into form II within a few days.     

The In Vitro Dissolution of Theophylline from Different Types of Hard Shell Capsules

ABSTRACT

The in vitro dissolution of theophylline from two-piece hard shell capsules has been investigated using different types of capsule shells (gelatin, gelatin/polyethylene glycol, hydroxypropyl methylcellulose), different formulations, different capsule fill weights, and different tamping forces. Analysis of variance confirmed that the formulation and the capsule shell materials were the most important factors influencing drug dissolution. The maximum extent of drug dissolution was significantly increased when hydroxypropyl methylcellulose (HPMC) capsules were used. The mean dissolution time (MDT) was significantly reduced, indicating a faster dissolution rate of the drug from HPMC capsules. The addition of microfine cellulose to the formulations as filler reduced the MDT in all cases, whereas the addition of lactose monohydrate did not enhance drug dissolution. The study confirmed that a change from gelatin hard shell capsules to gelatin/PEG or HPMC hard shell capsules should not pose problems with respect to drug absorption or bioavailability.     

The in vitro dissolution of theophylline from different types of hard shell capsules

The in vitro dissolution of theophylline from two-piece hard shell capsules has been investigated using different types of capsule shells (gelatin, gelatin/polyethylene glycol, hydroxypropyl methylcellulose), different formulations, different capsule fill weights, and different tamping forces. Analysis of variance confirmed that the formulation and the capsule shell materials were the most important factors influencing drug dissolution. The maximum extent of drug dissolution was significantly increased when hydroxypropyl methylcellulose (HPMC) capsules were used. The mean dissolution time (MDT) was significantly reduced, indicating a faster dissolution rate of the drug from HPMC capsules. The addition of microfine cellulose to the formulations as filler reduced the MDT in all cases, whereas the addition of lactose monohydrate did not enhance drug dissolution. The study confirmed that a change from gelatin hard shell capsules to gelatin/PEG or HPMC hard shell capsules should not pose problems with respect to drug absorption or bioavailability.     

Central composite rotatable design for optimization of budesonide-loaded cross-linked chitosan–dextran sulfate nanodispersion: characterization,in vitro diffusion and aerodynamic study

Budesonide is a BCS class II drug with low water solubility (0.045?mg/mL) and low oral bioavailability (6–8%) due to high first pass effect. The aim is to prepare cross-linked chitosan–dextran sulfate nanoparticles and/or nanodispersion. Nebulizable cross-linked nanodispersion was prepared by the solvent evaporation technique and characterized through XRPD, FTIR, mean particle size (MPS), polydispersity index (PDI), zeta potential (ZP), drug loading, entrapment efficiency, SEM, % production yield, in vitro diffusion, aerodynamic and stability study. The optimization of formulation was done by using central composite rotatable design to study the effect of independent variables, concentration of chitosan (X1) and concentration dextran sulfate (X2) on the dependent variables, MPS (Y1), drug loading (Y2) and % CDR (% cumulative drug release) (Y3). The MPS, PDI, and ZP of budesonide-loaded nanoparticles were 160.8?±?0.27?nm, 0.36?±?0.04, and 13?±?0.894?mV, respectively. The percent drug loading of all the batches was found in range of 10–16%. The emitted drug in target region (alveoli) was measured by using HPLC and it was found to be 18.26%. It was found that, nanodispersion had the optimum in vitro aerodynamic behavior. Stability study results showed no significant change in MPS, PDI, ZP, and % CDR after three month storage. In conclusion, cross-linked chitosan–dextran sulfate nanoparticles had properties suitable for nebulizable dispersion of increased drug loading, in vitro drug release and avoiding the first pass effect.     

Peculiarities in thermal evolution of precipitated amorphous calcium phosphates with an initial Ca/P ratio of 1:1

Thermal evolution of amorphous calcium phosphate (ACP) powder from a fast nitrate synthesis with a Ca/P ratio of 1:1 were studied in the range of 20–980?°C. The powder consisted of amorphous dicalcium phosphate anhydrate (CaHPO₄) after heating to 200?°C. CaHPO₄ gradually condensed to amorphous calcium pyrophosphate Ca₂P₂O₇ (CPP) between 200 to 620?°C. Amorphous CPP crystallized at 620–740?°C to a metastable polymorph α′-CPP of the high-temperature phase α-CPP and β-CPP. The α′-CPP/ β-CPP phase ratio reached a maximum at 800?°C (60?wt% α′-CPP/40?wt% β-CPP), and α′-CPP gradually transformed to β-CPP at a higher temperature. Some β-TCP occurred at 900?°C, so that a three-phasic mixture was obtained in the powder heated to 980?°C. The occurrence of metastable α′-CPP is attributed to Ostwald’s step rule, and a mechanism for β-TCP formation is proposed. The advantages of prospective biomaterials from these powders are discussed.     

Pre-formulation studies of resveratrol

Context: Resveratrol, a natural compound found in grapes, has potential chemotherapy effects but very low oral bioavailability in humans.

Objective: To evaluate the solubility, pH stability profile, plasma protein binding (PPB) and stability in plasma for resveratrol.

Methods: Solubility of resveratrol was measured in 10 common solvents at 25?°C using HPLC. The solution state pH stability of resveratrol was assessed in various United States Pharmacopeia buffers ranging from pH 2 to 10 for 24?h at 37?°C. Samples were analyzed up to 24?h. Human PPB was determined using ultracentrifugation technique. Standard solutions of drug were spiked to blank human plasma to yield final concentrations of 5, 12.5 or 25?μg/mL for determination. Finally, stability of resveratrol in human and rat plasma was also assessed at 37?°C. Aliquots of blank plasma were spiked with a standard drug concentration to yield final plasma concentration of 50?μg/mL. Samples were analyzed for resveratrol concentration up to 96?h.

Results: Resveratrol has wide solubility ranging from 0.05?mg/mL in water to 374?mg/mL in polyethylene glycol 400 (PEG-400). Resveratrol is relatively stable above pH 6 and has maximum degradation at pH 9. The mean PPB of resveratrol is 98.3%. Resveratrol degrades in human and rat plasma in a first-order process with mean half lives of 54 and 25?h, respectively.

Conclusion: Resveratrol is more soluble in alcohol and PEG-400 and stable in acidic pH. It binds highly to plasma proteins and degrades slower in human then rat plasma.     

A comparison of the puncturing properties of gelatin and hypromellose capsules for use in dry powder inhalers

This study investigates capsule puncture in dry powder inhalers. Gelatin and hydroxypropylmethyl cellulose (HPMC) capsules (stored at 11 and 33% relative humidities) were punctured using a pin from a Foradil inhaler, with insertion force measurement via an Instron tester. In HPMC capsules, the force after capsule puncture reduced by half and then increased to a second maximum as the pin shaft entered the hole. In gelatin capsules, the postpuncture force reduced to zero, indicating shell flaps losing contact with the pin. At lower moisture contents, both capsules were less flexible. This provides a tool to measure the shell properties of inhalation capsules.