International Journal of Pharmaceutics 499 (2016) 20–28

Impact of formulation and process variables on solid-state stability oftheophylline in controlled release formulations$

Maxwell Korang-Yeboaha, Ziyaur Rahmana, Dhaval Shaha, Adil Mohammada,Suyang Wua, Akhtar Siddiquia, Mansoor A. Khana,b,*aDivision of Product Quality Research, Center for Drug Evaluation and Research, Food and Drug Administration, MD, USAbRangel College of Pharmacy, Texas A&M Health Science Center Reynolds Medical Building, Suite 159, College Station, TX 77843-1114, USA

A R T I C L E I N F O

Article history:Received 21 August 2015Received in revised form 10 November 2015Accepted 26 November 2015Available online 11 December 2015

Keywords:Solid-state stabilityDissolutionPseudopolymorphic transitionTheophylline

A B S T R A C T

Understanding the impact of pharmaceutical processing, formulation excipients and their interactions onthe solid-state transitions of pharmaceutical solids during use and in storage is critical in ensuringconsistent product performance. This study reports the effect of polymer viscosity, diluent type,granulation and granulating fluid (water and isopropanol) on the pseudopolymorphic transition oftheophylline anhydrous (THA) in controlled release formulations as well as the implications of thistransition on critical quality attributes of the tablets. Accordingly, 12 formulations were prepared using afull factorial screening design and monitored over a 3 month period at 40 �C and 75%. Physicochemicalcharacterization revealed a drastic drop in tablet hardness accompanied by a very significant increase inmoisture content and swelling of all formulations. Spectroscopic analysis (ssNMR, Raman, NIR and PXRD)indicated conversion of THA to theophylline monohydrate (TMO) in all formulations prepared by aqueouswet granulation in as early as two weeks. Although all freshly prepared formulations contained THA, thehydration–dehydration process induced during aqueous wet granulation hastened the pseudopoly-morphic conversion of theophylline during storage through a cascade of events. On the other hand, nosolid state transformation was observed in directly compressed formulations and formulations in whichisopropanol was employed as a granulating fluid even after the twelve weeks study period. The transitionof THA to TMO resulted in a decrease in dissolution while an increase in dissolution was observed indirectly compressed and IPA granulated formulation. Consequently, the impact of pseudopolymorphictransition of theophylline on dissolution in controlled release formulations may be the net result of twoopposing factors: swelling and softening of the tablets which tend to favor an increase in drug dissolutionand hydration of theophylline which decreases the drug dissolution.

Published by Elsevier B.V.

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International Journal of Pharmaceutics

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1. Introduction

Most pharmaceutical solids exist in more than one crystallineform or in a disordered amorphous state. Some crystalline drugshave the propensity of incorporating in their crystal latticesolvents; either in a stoichiometric or non-stoichiometric way(Hilfiker et al., 2006). The different solid forms exhibit dissimilarphysical, mechanical and chemical properties which may affecttheir processability during product manufacturing, and alterproduct performance, such as stability, dissolution, bioavailability

$ Disclaimer: The views and opinions expressed in this paper are only those of theauthors, and do not necessarily reflect the views or policies of the FDA.* Corresponding author at: Rangel College of Pharmacy, Texas A&M Health

Science Center Reynolds Medical Building, Suite 159, College Station, TX 77843-1114, USA. Fax: +1 979 436 0087.

E-mail address: mkhan@pharmacy.tamhsc.edu (M.A. Khan).

http://dx.doi.org/10.1016/j.ijpharm.2015.11.0460378-5173/Published by Elsevier B.V.

and clinical efficacy (Huang and Tong, 2004; Kobayashi et al., 2000;Raw et al., 2004; Yu et al., 2003). Also, pharmaceutical processessuch as wet granulation, drying, milling; compression andlyophilization can induce polymorphic transition duringmanufacturing. Conversely, judicious selection of formulationexcipients can be employed to retard or inhibit solid-statetransition during processing and storage (Airaksinen et al.,2004; Zhang et al., 2004).

Theophylline is a bronchodilator used in the management ofreversible airway obstruction associated with asthma and chronicobstructive pulmonary disease. Currently, the therapeutic use oftheophylline in developed countries is restricted to patients whosedisease conditions are poorly controlled due to the drug's higherincidence of side effects; nonetheless theophylline is the mostwidely used bronchodilator due to its lower cost (Barnes, 2003;ZuWallack et al., 2001). Theophylline exists either as a monoclinicchannel hydrate or an anhydrate. Additionally, anhydrous

Table 1DOE of formulations used (abbreviations used: IPA-isopropanol; DC-directcompression).

Pattern Polymer Diluent Granulating fluid

F1 �+� HPMC K4M LM IPAF2 +�� HPMC K100M LA IPAF3 ��+ HPMC K4M LA WaterF4 +++ HPMC K100M LM WaterF5 �++ HPMC K4M LM WaterF6 +�+ HPMC K100M LA WaterF7 ++� HPMC K100M LM IPAF8 ��� HPMC K4M LA IPAF9 22 HPMC K100M LM DCF10 21 HPMC K100M LA DCF11 12 HPMC K4M LM DCF12 11 HPMC K4M LA DC

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theophylline has been identified to exist in three different forms;Form I is the most stable state at high temperature, Form II, whichis used in pharmaceutical formulations is stable at roomtemperature and Form III the metastable anhydrous intermediate(Seton et al., 2010). However, the commonly encountered solidstate transition of theophylline during the pharmaceuticalmanufacturing process and product storage is the transpositionbetween anhydrous Form II (THA) and theophylline monohydrate(TMO) with or without Form III as an intermediate.

Ando et al. (1986) first reported the conversion of THA to TMOupon storage at 90% relative humidity (Ando et al., 1986). Thistransition was also reported to occur upon storage at a relativehumidity of 75% (Alvarez-Lorenzo et al., 2000; Phadnis andSuryanarayanan,1997; Zhu et al., 1996). Additionally, THA has beenshown to convert to the monohydrate form irrespective of thechoice of formulation excipient used, during wet granulation(Airaksinen et al., 2004; Jørgensen et al., 2004; Wikström et al.,2008). The formation of anhydrous Form III has also been identifiedupon drying of the wet theophylline granules (monohydrate)under low pressure (Nunes et al., 2006; Phadnis and Suryanar-ayanan, 1997; Tantry et al., 2007). These transitions are associatedwith decrease in the dissolution and drug bioavailability owing tothe lower solubility of the monohydrate crystals as well as anincrease in binding interaction between theophylline and formu-lation excipients (Alvarez-Lorenzo et al., 2000; Herman et al., 1988,1989; Rodriguez-Hornedo et al., 1992). Theophylline has a narrowtherapeutic window and is associated with a high incidence ofadverse events and sudden deaths (eHealthMe, 2015). Conse-quently, minor alterations in theophylline product quality mayhave significant impact on the clinical efficacy and toxicityobserved in patients. For this reason, a thorough understandingof the impact of the manufacturing process, excipient choice aswell as their interactions on the solid-state stability of theophyllineduring storage is vital.

Although several authors have reported on the hydration anddehydration of theophylline, most of these studies were eitherconducted in binary mixtures of theophylline and excipients or inimmediate release formulations. However, most marketed the-ophylline products are controlled release formulations. Secondly,the impact of these solid-state transitions during manufacturingon the storage stability of the product remains unexplained.

The present study was an attempt to investigate the impact ofexcipient selection, manufacturing process and their interactionson solid-state transitions of theophylline in controlled releaseformulation during storage and use. Physicochemical and spectro-scopic characterizations were carried to monitor for any solid-statetransitions as well changes in product quality attributes.

2. Materials and method

2.1. Materials

Hydroxypropyl methylcellulose K4M and K100M (Colorcon,Harleysville, PA, USA), theophylline anhydrous Form II (THA),magnesium stearate (MgS) (Sigma, St. Louis, MO, USA), lactosemonohydrate (LM) and anhydrous lactose (LA) (Foremost farms,Baraboo, WI, USA), Colloidal silicon dioxide (Aerosil 200)(Evonik,Parsippany, NJ, USA), polyvinylpyrrolidone (PVP K15, K30 and K90)(Sigma Aldrich, St. Louis, MO, USA) were used.

2.2. Methods

2.2.1. Design of experimentThe effect of formulation and process variables on solid-state

stability and product quality were assessed using a full factorialdesign. The most commonly used formulation excipients and

process variables were chosen for this study. The formulationsvariables studied were; the polymer viscosity/molecular weight(HPMC K4M and HPMC K100M) and the diluent (LA and LM). Theformulation composition was as follows: THA 53.33%, K4M/K100M33.33%, LA/LM 10.7%, Aerosil 0.1% and MgS 2.5%. In addition, theimpact of the manufacturing processes (wet granulation and directcompression) and the granulating fluid employed (water andisopropanol) during wet granulation were considered. Theexperimental design and data analysis was conducted with JMPsoftware version 11.1.1 from SAS (Cary, NC, USA). In all twelveformulations were prepared according to the experimental designshown in Table 1.

2.2.2. Granulation and tabletingMixing and granulation were performed with the KG-5 high

shear granulator/mixer (Key International, Cranbury, New Jersey,USA). Solid-state transitions during granulation were monitored byin-line Luminar 5030 AOTF-NIR probe (Sparks Glencoe, Maryland,USA) and offline X-ray powder diffractometry. The wet granuleswere dried at 50 �C until the moisture content was below 2%. Themoisture content of the dried granules was determined by loss ondrying (MB 45 moisture analyzer, Ohaus Corporation, Parsippany,NJ, USA). The dried granules were sieved, blended with magnesiumstearate and aerosil 200. The granules were compressed intotablets with a rotary tablet press using a 10 mm punch size (GlobePharma, New Brunswick, New Jersey, USA). The initial tablethardness was 6–8 kp for all the formulations.

2.2.3. Physicochemical characterizationMoisture content analysis was performed with Karl Fisher

V30 compact titrator from Mettler Toledo- (Columbus OH, USA)using Aquastar1 Comp-2 Karl fisher reagent (EMD Millipore,Billerica, MA, USA). About 100 mg of powdered sample was usedfor moisture analysis. tablet hardness was measured with the PTB11EP hardness tester (Pharma Test, Hainburg, Germany). Scanningelectron microscopy (JSM-6390 LV- JEOL, Tokyo, Japan) images ofthe tablets were taken before and after stability studies at amagnification of 100X. The dissolution profiles were obtained withUSP dissolution apparatus I (basket) at 100 rpm. The dissolutionmedia used was 900 ml of 0.05 M phosphate buffer pH 6.6 main-tained at 37 �C. Sample collection was done over 24 hrs andanalyzed for their theophylline content. HPLC analysis wasconducted with an Agilent 1260HPLC system equipped with anauto sampler, a quaternary pump, diode array detector set at271 nm wavelengths, and column temperature maintained at25 �C. A Zorbax1 eclipse plus C-18 column (4.6 � 100 mm, 3.5 mmpacking) was used with a mobile phase composition of 7%acetonitrile and 93% acetate buffer (10 mM pH 3.5) run isocraticallyat 1 ml/min.

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2.2.4. Spectroscopic characterizationRaman spectra of THA, TMO and the stability samples were

obtained with non-contact Raman probe (RamanRXN2TM Multi-Channel Raman Analyzer, Kaiser Optical System Inc., Ann Arbor, MI,USA). NIR spectra were also collected over the wavelength range of1100–2500 nm (FOSS NIR System Inc., Laurel, MD, USA) aspreviously described (Korang-Yeboah et al., 2015; Rahman et al.,2015a). X-ray diffraction and C-13 ssNMR spectra patterns weremeasured with Bruker D8 Advance (Bruker AXS, Madison, WI, USA)and Varian VNMR 400 spectrometer (Varian Inc. Palo Alto,California) respectively as described in earlier studies. (Rahmanet al., 2015b) The extent of transformation was quantified from theXRPD data by the univariate peak area approach using characteristicTHA and TMO peaks at 7.2, and 11.5 2u (Otsuka and Kinoshita, 2010).

3. Results

3.1. Spectroscopic characterization

The differences between THA and TMO were studied using NIR,Raman, XRPD and ssNMR. These differences were exploited inmonitoring for solid state transitions of theophylline duringmanufacturing and in storage.

3.1.1. NIRNIR spectra of THA, TMO, freshly prepared formulations and

stability samples are shown in Fig. 1. NIR absorption bands aremainly due to overtones and combination bands of C-H, O-H, N-Hand S-H bonds and hence are highly susceptible to the presence ofmoisture. THA and freshly prepared tablets showed combinationpeaks of water and ��OH vibration (first overtone) at 1930 nm and1450 nm respectively. However, these peaks are also common toLM and THA and not very useful in monitoring of pseudopoly-morphic changes. Anhydrate to hydrate transition of theophyllineanhydrous Form II led to the generation of newer peaks and shiftsin already present peaks. Notable was the presence of anabsorption maxima at 1970 nm (water of crystallization) whichwas absent in the initial samples. Variations in these peak maximawere used to monitor the solid state transition in the formulations.

3.1.2. Raman spectraRaman spectra of THA and freshly prepared tablets showed peaks

in the spectral regions of 3200–2800 cm�1 and 100–1750 cm�1.

Fig. 1. (A) Raw and (B) 2nd derivative NIR spectra of formul

The spectra consisted of stretching modes of C��H (2970 cm�1, and3120 cm�1), C¼O (1662 cm�1 and 1704 cm�1), C¼C (1610 cm�1),C¼N (1571 cm�1), O¼C��N (554 cm�1), ��CH3 deformation(1424 cm�1) and rocking bands (928 cm�1) (Ahlneck and Zografi,1990; Edwards et al., 2005; Jørgensen et al., 2002). Although Ramanspectroscopy is insensitive to the presence of water, hydration oftheophylline leads to changes in hydrogen bond interactions whichdirectly alter molecular vibrations. Transition of THA to TMO led toband modifications along the entire spectral range. The mostprominent modificationwas the replacement of the double carbonylpeaks at 1662 cm�1 and 1704 cm�1 with a single peak at 1686 cm�1

(Fig. 2). Also majority of the Raman bands shifted either to a higherwavelength or a lower wavelength. These variations were observedwith time in some formulations during storage at acceleratedstability conditions.

3.1.3. XRPD analysisThe XRPD pattern of THA, TMO, freshly prepared tablets and

stability samples are shown in Fig. 3. The diffraction curves of THAand all freshly prepared tablets closely resembled previouslyreported patterns for orthorhombic THA with characteristic peaksat 7.2� and 12.5� (Edwards et al., 2005). However, the XRPD patternof TMO showed distinctive peaks at 8.8�, 11.5� and 27� 2u and theabsence of characteristic THA peaks at 7.2�, and 12.5�. The presenceof excipients did not interfere with the XRPD peaks of THA or TMO.Consequently, variations in these peaks were used as the measureof the solid state stability of the formulations during manufactur-ing and storage.

3.1.4. ssNMRssNMR spectra for THA, freshly prepared formulation F3, TMO

and stability samples are shown in Fig. 4. The 13C ssNMR spectraassignments of the freshly prepared tablets were similar topreviously reported(Edwards et al., 2005; Nolasco et al., 2006).THA showed peaks due to carbonyl carbons C-6 and C-2 at155.12 ppm, 150.93 ppm, respectively and methine carbons, C-4 and C-8 at 146.14 ppm, 140.96 ppm correspondingly. In addition,peaks corresponding to methyl group at C-10 and the methinecarbon at position 5 were obtained at 29.46 and 107 ppm. The mostnotable difference in the spectra of the TMO crystals was observedas a shift of the carbonyl peaks from 150.93 ppm to 148.4 ppm.Anhydrate to hydrate transition of THA was monitored in the

ation F3 before and during accelerated stability studies.

Fig. 2. Changes in Raman spectra of formulations A. F1 and B. F3 during 12 weeks accelerated stability studies.

M. Korang-Yeboah et al. / International Journal of Pharmaceutics 499 (2016) 20–28 23

region of 160–130 ppm due to the absence of interferences fromthe excipients.

3.1.5. Process induced transitionsNIR spectra obtained in-line during wet granulation indicated

conversion of THA to TMO for formulations F3–F6. This wasdetected by the appearance of crystalline OH peaks at 1970 nm and1468 nm. XRPD analysis conducted off-line also confirmed thetransformation of THA to TMO when water was used forgranulation. XRPD diffractogram of the wet granules showed thepresence of characteristic TMO peaks at 8.8� and 11.5� and the lossof the distinct anhydrous peak at 7.1�. However, no transitions wereobserved when IPA was used as the granulating fluid or in directlycompressed formulations (data not shown). The observed tran-sitions were in agreement with already published studies onpseudo polymorphic transitions of theophylline (Airaksinen et al.,2004; Herman et al., 1988). In contrast to earlier studies, ovendrying resulted in conversion of TMO to THA without the formationof Form III (Airaksinen et al., 2004; Phadnis and Suryanarayanan,1997; Tantry et al., 2007). This difference could be attributed to thedifferences in pressure conditions and duration of the dryingprocess. Also, tablet compression did not alter the solid state formof the drug as no differences were observed in the XRPD patternsbefore and after tableting.

3.1.6. Physicochemical characterizationThere was a significant (p < 0.05) increase in tablet weight for

all 12 formulations after 3 months of accelerated stability testing(40 �C 75% RH). Additionally, all the formulations swelledsignificantly in both axial and radial directions, as indicated byincrease in tablet diameter thickness (about 15% and 4%respectively), and almost 7% increase in average tablet weight.

This was also accompanied by a statistically significant (p < 0.05)increase in tablet moisture content. The average moisture contentin F3, F4, F5 and F6 was about 6.32%, representing about a 4-foldincrease from the initial average value of 1.42%. Moreover, theaverage moisture content for F1, F2 and F7–F12 doubled from theinitial content of 1.40% to about 3.02% (Table 2).

Furthermore, the hardness of all the tablets dropped signifi-cantly after two weeks of storage with moderate changes observedafterwards. SEM images showed an increase in surface roughnessand tablet porosity due to surface erosion, gelation of the polymerand swelling of the tablets (Fig. 5).

3.1.7. Solid state stabilityAll spectra techniques employed showed the presence of TMO

in F3–F6 after two weeks of the accelerated stability studies.However there were no changes in the spectral patterns of F1,F2 and F7–F12. Anhydrate to hydrate conversion of THA to TMOduring storage was observed in all tablets prepared by wetgranulation by the appearance of characteristic peaks at 8.8,11.5 and 27� in the XRPD pattern. The ssNMR spectra also showedan extra carbonyl peak at 148.66 in addition to the two anhydrouscarbonyl peaks at 155.12 ppm and 150.93 ppm. The peak intensityof the carbonyl carbon due to theophylline hydration was found toincrease with time.

However, there were no transformations in directly compressedformulations and in formulations in which isopropanol was usedas the granulating fluid even after 12 weeks of accelerated stabilityconditions. There was about 18% pseudopolymorphic conversion informulations F3 and F4 and about 10% in F4 and F5 after two weeks.The transformation of THA to TMO in the tablets was made up ofthree phases. An initial phase of rapid transition was followed bythe next phase in which very little to no change was observed and

Fig. 3. PXRD pattern of formulations (A) F1 and (B) F3.

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the final phase from week 8 to 12 in which significant changes wereobserved in the extent of transformation. At the end of the studyperiod, about 90% of THA had converted to TMO in F3, F4 and F5;and 77% conversion in F6.

3.2. Dissolution studies

The mechanism of the drug release was determined from thedissolution profiles using the semi-empirical model developed byKorsmeyer et al. (1983). The release exponent (n) which describesthe drug transport mechanism was calculated from regressionanalysis using the equation

Mt

M1¼ Kn

t

where Mt/M1 is the fractional drug release and K, a constantincorporating structural and geometric characteristic of the tablet.An n value of 0.45 is indicative of diffusion controlled drug releasewhile swelling controlled drug release are characterized by an nvalue of 0.89. A value of n between 0.45 and 0.89 suggests themechanism of drug release is by anomalous transport. Thedissolution profiles of the formulations were well described bythe Korsmeyer–Peppas model with an R2 value greater than 0.99 inall samples. The average diffusional exponent n was 0.67 (0.64–0.73) indicating the transport mechanism of THA from theformulation was by a combination of diffusion-controlled andswelling-controlled release.

Additionally, the impact of the observed pseudopolymorphictransition of theophylline on the drug dissolution profile wasstudied by comparing the dissolution profiles of F3–F6 after12 weeks to the initial samples and unhydrated THA formulationsF1 and F2. In contrast to the dissolution profile of the initialsamples there was a moderate drop in dissolution in formulationsF–F5 after 12 weeks. However, the decrease in dissolution of F6 atthe 24 h time point was not as pronounced as in F3–F5 althoughover 75% of THA had converted to TMO. The extent of dissolutionwas lowered by 12.33% in F3, 13.70% in F4, 12.21% in F5 and about5.60% in F6. Conversely, there was an increase in the extent ofdissolution in F1 and F2 after the 12 week period (Fig. 6).

4. Discussion

Theophylline for the past seven decades has been the mostwidely used bronchodilator due to its lower cost. Although the fourdifferent forms of anhydrous theophylline have been identified sofar, anhydrous theophylline form II is the only form used inpharmaceutical preparations of theophylline due to its superiorstability at room temperature. The crystalline packing of theoph-ylline Form II is characterized by hydrogen bonding betweenN��H� � �N and two bifurcated hydrogen bonds between C��H� � �O,forming a bilayer structure. However, at higher storage humidity orduring aqueous granulation, the theophylline molecule undergoesdimerization in the presence of water to form a monoclinic channelhydrate. This leads to changes in the physicochemical

Fig. 4. ssNMR spectra of THA, TMO and formulations (A) F1 and (B) F3.

M. Korang-Yeboah et al. / International Journal of Pharmaceutics 499 (2016) 20–28 25

characteristics of the drug and ultimately drug quality attributessuch as stability, bioavailability and clinical efficacy. In the currentstudy, anhydrate to hydrate transition of THA was observed duringwet granulation using in-line NIR probes and off-line XRPD. Ovenheating led to reconversion of TMO to THA. However, unlike inprevious reports, the formation of anhydrous theophylline Form IIIas an intermediate was not observed. This could be attributed tothe longer duration of drying used and pressure differences.Although this hydration–dehydration transition seems innocuous,it had direct impact on the storage stability and product quality.

Theophylline formulations F3–F6 manufactured using aqueouswet granulation technique had significantly higher moisture

Table 2Moisture content, extent of pseudopolymorphic conversion of theophylline and hardne

Moisture content (% w/w)

Initial WK 2 WK 4 WK 8 WK 12

F1 1.41(�0.09) 2.22(�0.22) 2.75(�0.03) 3.08(�0.01) 3.79(�0.09)

F2 0.88(�0.01) 2.20(�0.08) 2.77(�0.07) 2.65(�0.34) 3.38(�0.01)

F3 1.42(�0.05) 4.28(�0.29) 5.94(�0.03) 6.24(�0.00) 7.30(�0.09)

F4 1.51(�0.06) 5.65(�0.17) 5.87(�0.03) 6.51(�0.17) 7.38(�0.00)

F5 1.48(�0.01) 4.59(�0.20) 5.72(�0.02) 6.27(�0.02) 7.57(�0.80)

F6 1.28(�0.01) 3.90(�0.11) 5.34(�0.15) 6.26(�0.05 7.41(�0.05)

F7 1.75(�0.28) 2.41(�0.04) 2.77(�0.09) 3.15(�0.01) 3.98(�0.20)

F8 1.22(�0.15) 2.39(�0.08) 2.64(�0.09) 2.99(�0.05) 3.66(�0.30)

F9 2.06(�0.10) 2.35(�0.34) 3.03(�0.20) 2.94(�0.01) 3.88(�0.04)

F10 1.03(�0.05) 1.95(�0.34) 2.92(�0.10) 3.00(�0.02) 4.01(�0.01)

F11 1.65(�0.10) 2.26(�0.08) 3.24(�0.27) 3.17(�0.07) 4.2(�0.28)

F12 1.15(�0.10) 1.94(�0.06) 3.12(�0.18) 3.24(�0.03) 4.28(�0.34)

content after 12 weeks of accelerated stability studies than indirectly compressed formulations and when isopropanol was usedfor granulation (Table 2). The hydration–dehydration process isknown to reduce both surface and bulk crystallinity of drugproducts(Hüttenrauch et al., 1985; Murphy et al., 2002). Since THAis moderately soluble in water, it dissolves during the wetgranulation process and precipitates as the monohydrate crystalsbut reconverts to a more amorphous form of THA upon drying.Upon drying, there is a loss of crystalline structure and formationof amorphous THA hence a drop in crystallinity. The absence ofmoisture and poor solubility of THA in isopropanol precludes thistransition in directly compressed formulations and when IPA was

ss of theophylline formulations over the study period.

Theophylline Monohydrate(%w/w) Hardness(kP)

WK 2 WK 4 WK 8 WK 12 Initial WK 12

– – – – 8.13(7.9–8.6) 4.05(3.1–4.6)– – – – 7.05(5.5–8.3) 4.50(3.8–5.2)18 72 73 88 6.75(6.0–7.7) 5.91(5.0–6.5)17 72 74 93 7.15(6.8–7.3) 6.22(5.8–6.2)12 67 65 88 7.88(7.0–8.5) 5.48(4.4–6.6)10 48 51 77 7.05(6.1–7.6) 4.50(3.4–5.7)– – – – 6.93(5.9–6.4) 3.54(3.1–3.9)– – – – 6.83(6.3–8.7) 4.58(3.8–5.2)– – – – 6.77(5.9–7.3) 3.25(3.0–3.4)– – – – 7.58(6.2–9.0) 3.55(3.2–3.9)– – – – 7.55(7.3–7.9) 3.50(3.1–3.9)– – – – 6.77(6.4–7.5) 3.31(2.9–3.5)

Fig. 5. SEM images of tablet surfaces before and after 12 weeks of accelerated stability studies.

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used as a granulating fluid. Earlier studies by Debnath andSuryanarayanan (2004) reported a reduction of drug crystallinityby 25% due to the hydration–dehydration process (Debnath andSuryanarayanan, 2004). This increase in amorphous content mightaccount for the significantly higher moisture uptake kinetics informulations F3–F6. Also, all formulations increased in tablet sizeand weight after 12 weeks of accelerated stability studies due tothe hygroscopic nature of the polymer. tablet hardness droppedsignificantly in all formulations. The surface erosion and cracksobserved in SEM images may be due to tablet swelling anddissolution of the polymer and drug in the sorbed water (Fig. 5).

Furthermore, tablets manufactured by aqueous wet granulationtechnique underwent anhydrate to hydrate transition as early as intwo weeks at accelerated stability conditions. About 90% of THA inF3–F5 had undergone anhydrate to hydrate transition at the end ofthe study and more than 75% of THA transformed to TMO in F6.However the rest of the formulations (directly compressed andgranulation with isopropanol) exhibited no change in the solidstate nature of THA after 12 weeks of accelerated stability studies.The significant difference in the stability of the formulations couldbe attributed to a combination of process induced factors. Thetransformation of THA to TMO is known to be preceded by the

dissolution of THA form II in sorbed water to form a supersaturatedsolution (Alvarez-Lorenzo et al., 2000; Ando et al., 1992; Otsukaet al., 1990; Zhu et al., 1996). The next stage of the transformationinvolves nucleation of the monohydrate crystals followed bycrystal growth until the drug concentration of the solution hasdecreased to the solubility of the stable form (theophyllinemonohydrate). Interestingly, the hydration–dehydration tends topromote each of these phases. First, the reduction in both surfaceand bulk crystallinity of THA results in a faster super saturation andsubsequently a higher rate of crystallization. Secondly, thepresence of seeds of the monohydrate crystals hastens the processby lowering the nucleation barrier required to advance from asupersaturated solution to crystal growth (Cacciuto et al., 2004;Giron, 2001; Giron et al., 1990; Kelton, 1991). A similar observationwas reported in phenylbutazone in which no solid statetransformation was observed after 3 years of storage, howeverin the presence of trace amounts of Form B, significant levels oftransformation was observed in only 6 months (Giron et al., 1990).Also, the anhydrate to hydrate transition of theophylline incontrolled release matrices of HPMC may involve three phases(Table 2). An initial phase in which a dramatic increase in the rateof transformation is observed followed by a tapering off period in

Fig. 6. Dissolution curves for hydrated and unhydrated formulations before and after 12 weeks of accelerated stability studies.

M. Korang-Yeboah et al. / International Journal of Pharmaceutics 499 (2016) 20–28 27

which no significant transformation and the final phase wherethere was a further increase in the extent of anhydrate to hydrateconversion. The initial higher rate of hydration of theophyllinecould be attributed to the faster reactivity of THA with the sorbedbulk water than the HPMC or water migration from HPMC. Theexistence of a moisture gradient between the tablet surface incontact with sorbed moisture and the dry inner core might accountfor the second phase in which no significant transition of THA toTMO is observed. This gradient limits the availability of moisture tothe unaltered THA. As the sorbed water seeps further into thematrix, an increase in the amount of TMO is observed once more asthe remaining THA reacts with the bulk sorbed water.

The DOE study showed the use of aqueous wet granulationtechnique as the single most important factor that affectsanhydrate to hydrate transition of theophylline in the controlledrelease formulations during storage. The polymer molecularweight, the diluent used and the interaction between theformulation factors did not have significant effect (p > 0.05) onthe transition of THA to TMO.

Furthermore, there was a drop in the dissolution of F3–F5,however, no significant change was observed in the dissolution ofF6. On the other hand there was an increase in dissolution of theunhydrated tablets. The extent at which the pseudopolymorphictransition of theophylline impacts the dissolution profile was notas remarkable as previously reported by Ando et al. (1995) inimmediate (IR) release formulations of theophylline in whichhydration of theophylline led to over 50% drop in dissolution (Andoet al., 1995). This may be due to the presence of factors that opposethe effects of theophylline hydration on drug dissolution. Theswelling and softening of the tablets due to moisture uptake favorsan increase in drug dissolution, in contrast, hydration of

theophylline leads to a decrease in dissolution due to a decreasein solubility and dissolution rate. In addition, hydration oftheophylline during storage leads to increase in binding betweentheophylline and cellulose polymers which causes a decrease indissolution (Herman et al., 1989). The observed effect on thedissolution is possibly the net results of the above factors. Intheophylline formulations F3–F5 the observed decrease waspossibly due to the dominating effects of theophylline hydrationand increase in theophylline polymer binding. In F6, these factorscould not override the effect due tablet swelling and the decreasein hardness hence lowering the impact of theophylline hydrationin F6.

5. Conclusion

The solid state stability of many pharmaceuticals during storageand in-use is highly affected by the processing factors employedduring manufacture, the choice of excipients and interactionsbetween these factors. For drugs with narrow therapeutic indexsuch as theophylline, minor alterations in the product quality mayeither result in loss of clinical efficacy or toxicity hence the need fora thorough understanding of how formulation excipients andprocess affects the storage stability. The use of aqueous wetgranulation led to hydrate formation of theophylline. Although thisprocess was reversible during drying, the hydration–dehydrationof theophylline significantly affected the solid state stability incontrolled release formulations through a sequence of events thatultimately increases the rate of hydrate conversion. Conversely, themolecular weight of HPMC, the diluent type and the interactionbetween these factors and process did not affect the rate ofanhydrous to hydrate transition. There was more than 10%

28 M. Korang-Yeboah et al. / International Journal of Pharmaceutics 499 (2016) 20–28

decrease in the dissolution rate of most of the hydrated tablets.However the clinical significance of this reduction needs to befurther evaluated as theophylline is a narrow therapeutic indexdrug. In addition, most spectroscopic techniques were effective inmonitoring and characterizing the anhydrate to hydrate transitionof theophylline in controlled release formulations. The authors arecurrently exploring various analytical techniques for quantifyingthese transitions in theophylline products.

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