AAPS PharmSciTech, Vol. 13, No. 4, December 2012 ( # 2012)
`DOI: 10.1208/s12249-012-9841-0
`
`Research Article
`
`Effect of Formulation Conditions on Hypromellose Performance Properties
`in Films Used for Capsules and Tablet Coatings
`
`Jaime Curtis-Fisk,1,3 Paul Sheskey,2 Karen Balwinski,2 Karen Coppens,2 Carol Mohler,1 and Jin Zhao2
`
`Received 13 May 2012; accepted 15 August 2012; published online 8 September 2012
`Abstract. This study investigated the effects of polymer dispersion and hydration conditions on hypro-
`mellose (HPMC) film properties, such as strength, oxygen permeability, water vapor transmission, clarity,
`and haze. The focus of the study was to build a better understanding of the impact that changes to HPMC
`dispersion and hydration conditions have on performance properties of the resulting films. This under-
`standing could potentially lead to more flexible formulation guidelines for formulators. Films of HPMC
`2906 (USP) were produced from aqueous solutions prepared using various formulation conditions.
`Results showed that tensile properties and oxygen permeability were not significantly affected by the
`variables used. The differences observed in water vapor transmission are unlikely to affect practical
`application of the material. However, the differences observed in clarity and haze at 50°C hydration
`temperature could affect the appearance of a capsule or coated tablet. Several methods were used to
`determine whether loss of optical properties was due to surface phenomena or bulk defects within a film.
`Results indicated that the cloudy appearance was primarily due to surface roughness. Based on this
`information, there is some flexibility in formulation conditions; however, hydration temperatures greater
`than 25°C are not recommended.
`
`KEY WORDS: film properties; formulation conditions; HPMC; hypromellose; polymer hydration.
`
`INTRODUCTION
`
`Hypromellose (HPMC) is a common excipient used in
`pharmaceutical films, such as tablet coatings and hard capsule
`shells. The process of preparing formulations of HPMC to
`produce films that meet high-quality requirements can be an
`exacting process. Standard preparation protocols call for the
`polymer to be first dispersed in hot water (>80°C) and then
`hydrated at lower temperatures (<10°C) (1). If the powder is
`added directly to cold water, lumps may form in which the
`outer layer of polymer begins to hydrate, forming a shell
`around the dry powder, which can result in extended polymer
`hydration times.
`Such exacting formulation conditions can be difficult
`to maintain, prompting a desire from formulators for more
`flexibility in the formulation process. The focus of this
`study was to build a better understanding of HPMC dis-
`persion and hydration, and the impact that changes to
`these processes have on the performance properties of
`the resulting films. A secondary emphasis was to deter-
`mine if
`the recommended formulation conditions for
`
`1 Liquid Formulations and Actives Delivery, The Dow Chemical
`Company, 1712 Bldg., Midland, Michigan, USA.
`2 Dow-Wolff Cellulosics, The Dow Chemical Company, Midland,
`Michigan, USA.
`3 To whom correspondence should be addressed. (e-mail:
`jlcurtisfisk@dow.com)
`
`HPMC could be broadened to make the formulation pro-
`cess more flexible.
`
`BACKGROUND
`
`Several film properties are assessed when considering
`formulations for film-forming polymers, including mechanical
`strength, permeation, and optical properties (2–5). Strength is
`a particularly important property for films used to form cap-
`sule shells or tablet coatings. The film must be able to protect
`the contents during filling, packaging, shipping, and storage
`processes.
`In addition to mechanical strength, low oxygen perme-
`ability and water vapor transmission are desired properties for
`capsule shells, since certain active pharmaceutical ingredients
`react with either water or oxygen. Gasses travel through the
`films by two methods, capillary flow and diffusion. Capillary
`flow occurs when a gas passes through pores within a film.
`Transmission of water vapor occurs when the substance dis-
`solves on the surface, diffuses through the film, and evapo-
`rates on the other side (6). Both processes are affected by the
`structure of the polymer composing the film and the affinity of
`the gas to the material. For example, water vapor would have
`high transmission through a hydrophilic material such as
`HPMC. Capillary flow would be increased by defects within
`the film that allow the gas to easily pass through. The presence
`of additives or moisture in the film can also affect the
`
`1530-9932/12/0400-1170/0 # 2012 American Association of Pharmaceutical Scientists
`
`1170
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`HPMC Formulation Conditions
`
`1171
`
`interaction of the gas with the material and therefore the per-
`meation/transmission rates. For example, the rate of oxygen
`permeation through an HPMC film is sensitive to the humidity
`of the testing conditions (7).
`Although strength and gas permeation/transmission prop-
`erties are critical to protecting the contents of a capsule or tablet,
`the initial perception of the customer will be based on the
`appearance of the film. In cases where a clear film is desired, a
`lack of clarity or the presence of haze would be a negative
`feature. Typically, as clarity decreases, haze increases. Clarity
`is determined by small-angle light scattering; haze is determined
`by large-angle light scattering.
`Poor optical quality can be due to defects that exist either
`on the surface or within the bulk of the film (8). Inconsistent
`structure within the bulk of the film can lead to a non-uniform
`refractive index, resulting in poor optical quality. Crystallization
`within the film can also create defects that will alter the optical
`properties of the material (9–11).
`Several methods exist for investigating the source of poor
`optical quality. Optical properties can be compared to film
`thickness. If the defects lie on the surface of the film, these
`properties would remain constant as film thickness is varied. If
`the reason for poor optical quality is within the bulk of the
`film, optical properties would probably correlate with film
`thickness. An alternative method is to coat the surface of the
`film with oil that has a refractive index similar to the film
`material. The oil will fill any surface defects but not affect
`those within the bulk of the film. If the optical quality of the
`oil-coated film improves, this would indicate the defects are on
`the surface. Analysis of surface morphology may be con-
`ducted through either contact (profilometry) or noncontact
`(interferometry) methods, both of which provide information
`on surface roughness. Increased surface roughness can affect
`both the optical properties of the film and also the visual
`appearance of the film texture (12).
`
`MATERIALS AND METHODS
`
`Materials
`
`The films in this study were made from low-viscosity (low
`molecular weight) HPMC 2906 (METHOCEL1 F5 Premium
`cellulose ether, The Dow Chemical Company, Midland, MI,
`USA).
`
`Hypromellose Solution Preparation
`
`All formulations were prepared using the conventional
`“hot–cold” method in which the HPMC powder is dispersed in
`water at an elevated temperature and then cooled for hydra-
`tion of the polymer (1). Temperature during dispersion and
`hydration was maintained with a water bath monitored with a
`thermocouple to within a degree of the target. The solutions
`(20% HPMC in water) were prepared by quickly adding the
`powder to a 500-mL jar containing water at the dispersion
`temperature (60 or 80°C) and equipped with a three-blade
`
`1 ™Trademark of The Dow Chemical Company (“Dow”) or an affil-
`iated company of Dow
`
`stirring shaft. During the powder addition, the stirring rate
`was set to 600 rpm to efficiently draw the powder into the
`water by creating a vortex. After powder addition, the rate
`was reduced to 400 rpm to reduce the number of bubbles
`incorporated into the solution. Stirring during the dispersion
`phase was continued for 1 h. Following dispersion, the water
`bath was adjusted to the hydration temperature (4°C, 25°C, or
`50°C). Timing of the hydration phase began once the solution
`had reached the appropriate temperature, typically 5–15 min,
`depending on the magnitude of the temperature drop. Once
`the hydration temperature was achieved, stirring was stopped.
`Samples were removed at 1, 3, and 5 h. Before films were
`prepared, dissolved gas was removed from the solution by
`placing the sample under vacuum for 2 min followed by cen-
`trifugation at 2,800 rpm for 5 min to remove bubbles.
`
`Preparation of Films
`
`Films were hand-drawn on glass plates using the 40-mil
`gap option of a multiple clearance application square (BYK,
`Columbia, MD, USA). The HPMC solution (at hydration
`temperature) was poured into the square near the edge of
`the glass plate, and the square was pulled steadily down the
`glass to minimize formation of defects. Films were dried over-
`night under ambient conditions, typically about 21°C with
`relative humidity ranging from 20% to 40%. Thermogravi-
`metric analysis (TGA 2950, DuPont Instruments, Cincinnati,
`OH, USA) was used to confirm that the water content of the
`films was consistent with dry films, about 6% moisture con-
`tent. After removal from the glass, the films were stored in a
`laboratory with constant temperature and humidity (22°C,
`50% relative humidity) for at least 18 h prior to analysis to
`equilibrate the water content. For all film testing, samples
`were taken from areas of the film that did not contain any
`obvious defects or bubbles. Film thickness is reported in the
`unit mil or 0.001 in.
`
`Tensile Strength Measurements
`
`Tensile strength was measured using an Instron universal
`testing machine (Model 4201/5501R, Instron, Norwood, MA,
`USA) following ASTM method D-638 with an extension rate
`of 0.2 in./min. Samples were cut from the film using a type IV
`die. Thickness of each sample was measured prior to testing
`and was generally between 4 and 5 mil.
`
`Oxygen Permeability and Water Vapor Transmission Rate
`Measurements
`
`Oxygen permeability was measured on an Ox-Tran 2/21
`system (Mocon, Minneapolis, MN, USA). Test conditions were
`10% oxygen, 23°C, and 50% relative humidity. Films were
`masked to a 1-in. diameter testing area, which was normalized
`to a 5 cm2 testing area in final calculations. The permeability was
`normalized for the film thickness to yield a value with units of
`cc∙mil/[100 in2∙day∙atm]. Four samples were tested for each
`condition at an HPMC hydration time of 5 h.
`Water vapor transmission rates were measured using a
`dry cup method. Two grams of calcium chloride was weighed
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`1172
`
`Curtis-Fisk et al.
`
`1 hour hydration
`3 hours hydration
`5 hours hydration
`
`1900
`
`1850
`
`1800
`
`1750
`
`1700
`
`1650
`
`1600
`
`1550
`
`1500
`
`Young's Modulus (MPa)
`
`60/4
`
`60/25
`
`80/25
`80/4
`60/50
`Formulation Conditions
`Dispersion Temp. (°C)/Hydration Temp. (°C)
`Fig. 1. Effect of formulation conditions on Young’s modulus
`
`80/50
`
`into a 4-oz jar and allowed to equilibrate at 50% relative
`humidity and 73°F with a closed cap for 1 h. Next, a small
`amount of vacuum grease was placed around the edge of the
`jar’s mouth. Films were cut into 1.3-in. diameter circles using a
`metal punch. The film samples were placed over the mouth of
`the jar, and a 1-in. diameter, open-hole lid was placed on top.
`The lid was tightened enough to form a seal, but not
`enough to damage the film. The jars were then placed
`in a temperature/humidity chamber equipped with an En-
`viron-Cab controller (Lab-Line Instrument, Inc., Melrose
`Park, IL, USA) set at 75% relative humidity and 25°C.
`The total weight of the jar, lid, film, and calcium chloride
`was recorded and measured again approximately every
`24 h for 5 days. The rate was normalized for film
`
`thickness and to a 5 cm2 testing area to yield a value
`with units of grams per meter per square centimeter per
`minute. Four samples were tested for each condition at an
`HPMC hydration time of 5 h.
`
`Clarity and Haze Measurements
`
`Clarity was measured on a clarity meter (Model CL-100,
`Zebedee Corporation, Moore, SC, USA). Haze was measured
`at four places on each film using a Haze-guard unit (BYK
`Gardner, Columbia, MD, USA) equipped with a CIE-C light
`source. The thickness of each film was measured prior to
`analysis.
`
`1 hour hydration
`3 hours hydration
`5 hours hydration
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`Maximum Tensile Stress (MPa)
`
`60/4
`
`60/25
`
`80/25
`80/4
`60/50
`Formulation Conditions
`Dispersion Temp. (°C)/Hydration Temp. (°C)
`Fig. 2. Effect of formulation conditions on maximum tensile stress
`
`80/50
`
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`HPMC Formulation Conditions
`
`1173
`
`1 hour hydration
`3 hours hydration
`5 hours hydration
`
`10
`
`0123456789
`
`Maximum Tensile Strain (MPa)
`
`60/4
`
`60/25
`
`80/25
`80/4
`60/50
`Formulation Conditions
`Dispersion Temp. (°C)/Hydration Temp. (°C)
`Fig. 3. Effect of formulation conditions on maximum tensile strain
`
`80/50
`
`Film Surface Property Measurements
`
`To check for surface vs bulk defects, a drop of sili-
`cone oil was placed on the surface of both the clear and
`cloudy films. Silicone oil has a refractive index near that
`of HPMC film (n~1.52). Microscopy was used to collect
`images of each film type (clear or cloudy) at five or 10 times
`magnification. Comparison of the areas coated with oil to those
`without can indicate if the defects are on the surface or within
`the bulk of the film.
`For surface roughness determinations, each film was
`mounted to a glass slide and imaged using a Tencor P-15 stylus
`profilometer (KLA-Tencor Corporation, Milpitas, CA, USA). A
`
`1,000×1,000 μm area was imaged with a 1.0-mg load, 200-μm/s
`scan speed, 50-Hz sampling rate, 4-μm y-spacing, and 131 μm/
`0.0781 Å range/resolution. Data were processed and analyzed
`using SPIP v.5.1.5 software (Image Metrology, Hørsholm, Den-
`mark). Images were plane-fit and filtered for noise before rough-
`ness analysis.
`A white light interferometer (Model NT9100, Wyko Cor-
`poration, Tucson, AZ, USA) was also used to analyze the
`surface characteristics of the films. To ensure that analysis
`was representative of the whole film, several locations on each
`film were tested, avoiding any areas of visible defects, such as
`bubbles. Each scan analyzes an area of approximately 0.1 x
`0.1 mm. The images presented are of representative locations
`
`80
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`(cc·mil/[100 in2·day·atm])
`
`Oxygen Permeability
`
`60/4
`
`80/4
`60/50
`Formulation Conditions
`Dispersion Temp. (°C)/Hydration Temp. (°C)
`Fig. 4. Effect of formulation conditions on oxygen permeability at 5 h hydration time, 50%
`RH, 23°C
`
`80/50
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`1174
`
`Curtis-Fisk et al.
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`1.8
`
`1.6
`
`1.4
`
`1.2
`
`1
`
`0.8
`
`0.6
`
`0.4
`
`0.2
`
`0
`
`(g·m/cm2·min x 10-3)
`
`Water Vapor Transmission Rate
`
`60/4
`
`80/4
`60/50
`Formulation Conditions
`Dispersion Temp. (°C)/Hydration Temp. (°C)
`Fig. 5. Effect of formulation conditions on water vapor transmission at 5 h hydration time,
`75% RH, 25°C
`
`80/50
`
`and numerical results show an average of at least three
`locations.
`
`RESULTS AND DISCUSSION
`
`Film Mechanical Properties
`
`Mechanical strength is a key property for excipient films
`used in capsules and tablet coatings. The capsules must be
`able to withstand the filling process and both capsules and
`tablet coatings must provide protection of the contents during
`shipping and storage. In this study, tensile properties were
`used as a measure of strength. Figure 1 shows average Young’s
`
`modulus for each formulation condition. There were no clear
`trends when the dispersion or hydration temperature was
`varied, and extending the hydration time from 1 to 3 or 5 h
`had no significant effect on the modulus. This data set was
`analyzed using the Tukey–Kramer test for statistically rele-
`vant similarity, and results showed no difference between the
`data from any formulation condition to a 95% confidence
`level. Maximum tensile stress and strain were also measured,
`with the data compared in Figs. 2 and 3. These properties
`exhibited a relatively large standard deviation compared to
`Young’s modulus, an inherent difficulty when measuring ten-
`sile properties of films, but there were no clear trends across
`the range of conditions tested.
`
`1 hour hydration
`3 hours hydration
`5 hours hydration
`
`60/25
`
`80/25
`80/4
`60/50
`Formulation Conditions
`Dispersion Temp. (°C)/Hydration Temp. (°C)
`Fig. 6. Effect of formulation conditions on film clarity
`
`80/50
`
`60/4
`
`100
`
`90
`
`80
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`Clarity (%)
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`HPMC Formulation Conditions
`
`1175
`
`1 hour hydration
`3 hours hydration
`5 hours hydration
`
`60/25
`
`80/25
`80/4
`60/50
`Formulation Conditions
`Dispersion Temp. (°C)/Hydration Temp. (°C)
`Fig. 7. Effect of formulation conditions on film haze
`
`80/50
`
`60/4
`
`4
`
`3.5
`
`3
`
`2.5
`
`2
`
`1.5
`
`1
`
`0.5
`
`0
`
`Haze (%)
`
`Oxygen Permeability and Water Vapor Transmission
`
`Both oxygen and water vapor can affect the contents of
`capsules and tablets, making low permeability for these sub-
`stances a highly desirable property. Oxygen permeation
`through hypromellose films is known to be highly affected
`by the water content of the films (7), which is determined by
`the humidity of the testing conditions. For this study, humidity
`was held at a constant value of 50% for all measurements and
`therefore should not affect permeability results. However,
`even more than humidity, permeability is influenced by
`defects in the film that create pores through which the gas
`can transmit. Therefore, changes in polymer structure due to
`
`formulation conditions could be reflected by changes in oxy-
`gen permeability. Figure 4 shows that oxygen permeability
`was not affected by the different formulation conditions stud-
`ied, indicating that no set of formulation conditions was more
`likely to produce a defect sensitive to oxygen permeation than
`another. Because no difference was seen between oxygen
`permeability at the low and high hydration temperatures and
`because this measurement is very time-consuming, hydration
`data were not collected at the middle hydration temperature,
`25°C.
`Water vapor transmission rate (WVTR) of films pro-
`duced from formulations dispersed at 60°C was higher for
`both hydration temperatures than formulations dispersed at
`
`4°C hydration temperature
`
`50°C hydration temperature
`
`100
`
`90
`
`80
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`Clarity (%)
`
`0
`
`1
`
`2
`
`4
`3
`Film Thickness (mil)
`Fig. 8. Clarity of films produced from HPMC solution hydrated at 4°C or 50°C
`
`5
`
`6
`
`7
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`Fig. 9. An oil test performed by placing a drop of oil on the surface of a cloudy and a clear film
`
`80°C (Fig. 5), a statistically significant difference with a confi-
`dence level of 95%. The average WVTR of formulations
`hydrated at 50°C was higher than those hydrated at 4°C,
`within the same dispersion condition, but the large standard
`deviations limited the amount of statistically significant con-
`clusions that could be drawn from these data. Again, this
`measurement was limited to the high and low hydration tem-
`peratures because the additional time required to collect data
`at the middle temperature, 25°C, was not likely to further
`elucidate the results. The introduction of this paper describes
`two methods by which water vapor can travel through a
`film, by capillary flow through pores (defects) in the film,
`or by a process in which the vapor diffuses through the
`polymer structure of the film. Either of these mechanisms
`could be affected by a change in the film. Defects in the
`film surface will give more opportunity for capillary flow,
`and a change in the polymer structure composing the film
`may affect
`the interaction of water with the polymer,
`therefore changing the diffusion rates (6). Despite the
`variability observed with dispersion conditions, based on
`
`the authors’ experience, these results are not likely to affect
`practical application of the material.
`The oxygen permeation and water vapor transmission
`analysis of the film produced from different dispersion and
`hydration conditions indicate that these properties do not vary
`enough within this range of conditions to be a primary mea-
`sure of film quality. This is a positive result in regards to
`formulation flexibility when preparing films, but not a good
`discriminating factor.
`
`Clarity and Haze
`
`Varying the dispersion temperature did not affect either
`clarity or haze (Figs. 6 and 7), but when the formulation was
`hydrated and cast at 50°C, the films had a much lower level of
`clarity relative to hydration at 4°C or 25°C (Fig. 6). Clarity of
`films hydrated at 50°C did not appreciably change when the
`hydration time was lengthened. Analysis of the clarity results
`using the Tukey–Kramer test revealed statistically significant
`differences only between hydration temperatures, not when
`
`Fig. 10. White light interferometry images of a clear film and a cloudy film. All images are
`of a 95×127 μm area of film
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`HPMC Formulation Conditions
`
`1177
`
`Table I. Surface Roughness Parameters, Mean Deviation (Sa) and
`Root Mean Square Deviation (Sq), Obtained with use of a White
`Light Interferometer or Profilometer
`
`Method
`
`Interferometry
`
`Profilometry
`
`Film
`
`Sa (nm)
`
`Sq (nm)
`
`Clear, glass side
`Cloudy, glass side
`Clear, exposed side
`Cloudy, exposed side
`Clear, exposed side
`Cloudy, exposed side
`
`5
`6
`10
`140
`10
`400
`
`6
`8
`20
`170
`20
`500
`
`dispersion temperature or hydration time was changed, with
`the exception of the samples hydrated at 50°C. The clarity
`values for this set of data were low enough that the films
`would not be usable for capsules or tablet coatings. Haze
`analysis of the films revealed the same trends, a decrease in
`optical quality (increase in haze) with increased hydration
`temperatures (Fig. 7). Even though all haze values were low,
`when the hydration temperature was increased to 50°C the
`haze results were higher at a statistically significant level com-
`pared to conditions at 4°C or 25°C, demonstrated by the
`Tukey–Kramer test.
`Clarity was also measured on films with a range of thick-
`nesses. Films were cast at wet thicknesses ranging from 5 to
`50 mil, producing dry films from 0.5 to 8 mil. There was no
`indication that the clarity varied across this range of film
`thicknesses for either the clear films (formulation hydrated
`at 4°C) or the cloudy films (hydrated at 50°C; Fig. 8).
`The reason for the difference observed in optical quality
`between films produced at different formulation conditions is
`not obvious. A key question is whether the optical effects are
`surface effects or lie within the bulk of the HPMC film. Sev-
`eral internal Dow studies have determined that, in the case of
`polyethylene films, observed haze is either due to surface
`roughness caused as the film exits the die or from crystalliza-
`tion near the film surface. For HPMC, surface defects could
`occur as the casting bar is pulled across the formulation to
`create the films. At higher hydration temperatures, the solu-
`tion is above the temperature at which thermal gelation occurs
`and this more viscous, gelled solution is less likely to produce a
`smooth surface upon film casting. This is consistent with gen-
`eral HPMC solution properties in which the viscosity initially
`decreases upon heating, but at a point referred to as the
`“incipient gelation temperature” the viscosity undergoes a
`steep rise (13). For an HPMC formulation containing 20%
`METHOCEL F5 Premium cellulose ether, this point is near
`
`36.5°C. Casting films from the more viscous solution above
`this temperature may be contributing to the observed surface
`defects. In addition, higher hydration temperatures may slow
`the hydration process or not allow for complete hydration.
`This may change the polymer structure within the film, which
`could reduce optical quality.
`
`Bulk vs. Surface Optical Effects
`
`The fact that there was no change in clarity across a range
`of film thicknesses for either the clear films (formulation hydrat-
`ed at 4°C) or the cloudy films (hydrated at 50°C; Fig. 8) is strong
`evidence in support of a surface effect. A simple microscopy test
`provided further support. When a drop of oil placed on the clear
`and cloudy films was examined under a light microscopy, the oil
`layer removed the appearance of defects on the cloudy film,
`smoothing any roughness on the surface and resulting in fewer
`defects to deflect the light. On the clear film, the oil did not have
`an obvious impact on the appearance. These results give further
`evidence that the lower optical quality of the cloudy films is due
`to surface effects (Fig. 9).
`White light interferometry and profilometry were used to
`measure surface roughness. Figure 10 shows the interferome-
`try analysis of a clear film sample hydrated at 4°C and a
`cloudy film hydrated at 50°C. Table I lists the average numer-
`ical results. The images and surface roughness parameters
`reveal a difference between the side of the film dried against
`the glass substrate and the side exposed to air, and an even
`greater difference between the exposed surface of the clear
`and cloudy films. The surface roughness parameters Sa (aver-
`age height of the surface roughness) and Sq (root mean square
`of the roughness) target average deviation from the plane of
`the surface (11). The exposed side of the cloudy film exhibited
`values that were about 10 times greater than for the exposed
`side of the clear film. Sz and St both relate to the height differ-
`ence between the greatest peaks and valleys of the surface. The
`difference between the glass side of the clear and cloudy films
`was not as great for these parameters, but the cloudy film did
`appear to have more peaks than the clear film.
`Profilometry was used to examine another set of similar
`samples, examining only the side of the film exposed to air
`during drying. Figure 11 shows a three-dimensional image of
`each film. Note that the scale of the z-axis is different for each
`sample in order to show detail. The cloudy film is displayed with
`a surface depth of 3,300 nm, while the clear film, which was
`much smoother with smaller defects, is displayed at a surface
`depth of 200 nm. Data in Table I indicate a 40-fold increase in
`surface roughness for the cloudy film.
`
`Fig. 11. Three-dimensional image of each film
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`1178
`
`Curtis-Fisk et al.
`
`These results indicate that hydration temperature was the
`critical factor affecting optical quality, increasing surface
`roughness of the HPMC film. Although the upper limit for
`hydration temperature in this study (50°C) is well above nor-
`mal solution preparation temperatures, the positive results
`seen at 25°C hydration could enable more flexibility in the
`formulation process, which now requires a hydration temper-
`ature of <10°C.
`
`CONCLUSIONS
`
`Hypromellose films were prepared using a range of dis-
`persion and hydration conditions. Although physical proper-
`ties of the films were generally unaffected by the range of
`conditions tested, optical properties were negatively affected
`by high hydration temperatures (50°C). A more moderate
`increase in hydration temperature to 25°C did not affect opti-
`cal properties. Film clarity was not affected by film thickness,
`indicating that the change in optical properties was a surface
`effect. This finding was confirmed by microscopy, interferom-
`etry, and profilometry tests, which indicated surface roughness
`as the cause of lower optical quality. Therefore, although there
`can be some flexibility in the formulation conditions for HPMC
`solution preparation, hydration temperatures greater than 25°C
`are not recommended.
`
`ACKNOWLEDGMENTS
`
`We would like to thank Bob Gunther and Sheri Clark for
`assistance with measuring clarity and haze properties of the
`films, Ellen Keene for conducting the microscopy oil test, and
`Meagan Blake for profilometry analysis of the films.
`
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