- Email: [email protected]
Development of Methamphetamine Abuse–Deterrent Formulations Using Sucrose Acetate Isobutyrate
Journal Pre-proof Development Of Methamphetamine Abuse-Deterrent Formulations Using Sucrose Acetate Isobutyrate Sathish Dharani, Sogra F. Barakh Ali, Hamideh Afrooz, Eman M. Mohamed, Phillip Cook, Mansoor A. Khan, Ziyaur Rahman PII:
S0022-3549(19)30808-1
DOI:
https://doi.org/10.1016/j.xphs.2019.12.003
Reference:
XPHS 1819
To appear in:
Journal of Pharmaceutical Sciences
Received Date: 20 August 2019 Revised Date:
6 November 2019
Accepted Date: 3 December 2019
Please cite this article as: Dharani S, Barakh Ali SF, Afrooz H, Mohamed EM, Cook P, Khan MA, Rahman Z, Development Of Methamphetamine Abuse-Deterrent Formulations Using Sucrose Acetate Isobutyrate, Journal of Pharmaceutical Sciences (2020), doi: https://doi.org/10.1016/j.xphs.2019.12.003. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc. on behalf of the American Pharmacists Association.
1 2 3
DEVELOPMENT OF METHAMPHETAMINE ABUSE-DETERRENT FORMULATIONS USING SUCROSE ACETATE ISOBUTYRATE
4
Sathish Dharani1, Sogra F. Barakh Ali1, Hamideh Afrooz1, Eman M. Mohamed1,2, Phillip Cook3,
5
Mansoor A. Khan1, Ziyaur Rahman1*
6
1-Irma Lerma Rangel College of Pharmacy, Texas A&M Health Science Center, Texas A&M
7
University, College Station, TX 77843, USA
8
2-Department of Pharmaceutics, Faculty of Pharmacy, Beni-Suef University, Egypt.
9
3-Eastman Chemical Company, Kingsport, TN 37662, USA
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34
*-Corresponding author Ziyaur Rahman, Ph.D. Associate Professor 310 Reynolds Medical Sciences Building College Station, Texas 77843-1114 Email: [email protected] Phone: 979-436-0873 Fax: 979-436-0087
35
ABSTRACT
36
The objective of the present research was to investigate application of sucrose acetate isobutyrate
37
(SAIB) in the development of a Meth-Deterrent formulation in combination with polyethylene
38
oxide (PolyoxTM) and hydroxypropyl methylcellulose (HPMC). The formulations were
39
prepared by granulating pseudoephedrine hydrochloride (PSE), HPMC and PolyoxTM with an
40
ethanolic solution of SAIB and compressed into tablets followed by heat curing. The tablets were
41
characterized for surface morphology, crystallinity, drug distribution, hardness, particle size,
42
extraction, and dissolution. Hardness increased insignificantly, surface morphology indicated
43
cracking and crevices, and diffractograms showed an increase and a decrease in drug and
44
PolyoxTM crystallinity, respectively, after heat curing. PSE, PolyoxTM and SAIB distribution
45
was uniform as indicated by NIR image. The drug extraction varied from 69.5-77.8, 90.3-106.5,
46
51.3-81.2 and 48.9-72.6% in water, ethanol, 0.1 N HCl and 0.1 N NaOH, respectively. The
47
dissolution was more than 85% in 9 hours from all the formulations. Thus, the addition of SAIB
48
to the formulation decreased the drug extraction in various solvents which has the potential to
49
decrease abuse of pseudoephedrine formulation for methamphetamine synthesis.
50
Key words: Meth-Deterrent formulations, Pseudoephedrine hydrochloride, PolyoxTM, HPMC,
51
solvent extraction, dissolution, Sucrose acetate isobutyrate, SAIB
52 53 54 55 56 57 58 59 60 61
62
INTRODUCTION
63
The United States has a serious problem of drug abuse which leads to social, economic and
64
medical issues.1,2 Abusers can abuse prescription and over-the-counter (OTC) drug products. It
65
is much easier and inexpensive to get over-the counter (OTC) than prescription medicines. OTC
66
drug products are available in supermarkets, drugstores and convenience stores. There is
67
widespread but wrong belief that these drugs must be less dangerous than those found behind the
68
pharmacy counter because one need a prescription. The top ten OTC drug products abused by
69
teens and adults are dextromethorphan, loperamide, pain relievers (acetaminophen and
70
ibuprofen), caffeine medicines and energy drinks (NoDoz and 5 Hour Energy), diet pills
71
(stimulant found in diet pills are phenylpropanolamine, ephedrine, and ephedra), laxative and
72
herbal diuretics (water pills, includes uva-ursa, golden seal, dandelion root, rose hips, and others
73
to lose weight), motion sickness pills (dimenhydrinate (Dramamine) or diphenhydramine
74
(Benadryl)), sexual performance medicines, pseudoephedrine hydrochloride (PSE), herbal
75
ecstasy (the main ingredient is ma huang (ephedra) and other herbal e.g. Salvia, Nutmeg).3-5
76
Since they are legal and easy to find, OTC drugs are also easy to abuse. Abuse of OTC
77
medicines is most common among teens between the ages of 13 and 16.4 They know they can
78
find a cheap "high" right in their family's or friend's medicine cabinet. Young adults have also
79
abused OTC medicines, particularly in combination with other medicines, alcohol, and illegal
80
drugs, which increases the risks of serious side effects.3-5
81
PSE is a nasal decongestant and stimulant, and commonly found in many cold medicines e.g.
82
Sudogest and Nexafed etc.6 It can be diverted to synthesize methamphetamine (MET), a potent
83
stimulant and addictive compound. Its chemical structure is similar to amphetamine. PSE
84
(C10H15NO) and MET (C10H15N) differ by oxygen atom which can be removed by chemical
85
reduction reaction
86
with hyperactivity and exogenous obesity, and is commercially available as a tablet dosage
87
form.9 It is abused as a central nervous system stimulant to cause an excitable, hyperactive
88
feeling.10,11 However, PSE can also be abused without chemical conversion to MET.12,13 People
89
have taken PSE to lose weight,14,15 and athletes have misused the medicine to increase their state
90
of awareness and to get them “pumped up” before a competition.16-19 Abuse of PSE is low
91
compared to other OTC products due to federal law requiring it to be kept behind the pharmacy
92
counter, limiting the purchase quantity, and requiring photo identification prior to purchase.20
7,8
(Figure 1). MET has been approved by FDA for attentive deficit disorder
93
Additionally, Drug Enforcement Administration classified PSE under “List I of chemicals” to
94
further control diversion and misuse of PSE.21 Dangerous side effects of PSE include heart
95
palpitations, irregular heartbeats, and heart attacks. When combined with other drugs, such as
96
narcotics, PSE may trigger episodes of paranoid psychosis.22-24 Unlike opioids addiction/toxicity
97
treatment, there is no antidote for PSE or MET addiction/toxicity treatment.
98
To further cut down the access of pseudoephedrine from the pharmacy and hence reduce the
99
conversion of PSE into MET, pharmaceutical manufacturer(s) have developed novel
100
formulations called Meth-Deterrent formulations, which are a type of abuse deterrent
101
formulations.25 Currently, there are three PSE commercial products with Meth-Deterrent claim:
102
Nexafed®26 (PSE, Nasal decongestant), Nexafed®26 (PSE and acetaminophen, Sinus pressure +
103
Pain) and Zephrex-D®27 (PSE, sinus pressure). However, the FDA has not approved nor
104
endorsed Meth-Deterrent claims.
105
technologies called Tarex® and Impede®, respectively. Tarex® is based on lipid formulation
106
which provides resistance to PSE extraction (Tarex® technology)28. On the other hands, Impede®
107
is based on polymers matrix which forms a viscous mass when it comes in contact with aqueous
108
medium (Impede® technology)29. The objective of the present research was to investigate abuse
109
deterrent properties of Meth-Deterrent formulations based on polyethylene oxide (PolyoxTM) and
110
hydroxypropyl methyl cellulose (HPMC) with and without sucrose acetate isobutyrate
111
(BioSustane™, SAIB).25 PolyoxTM and HPMC are commonly found in opioid abuse-deterrent
112
formulations (OxyContin® label30; MorphaBond ERTM label31; ArymoTM ER label32; VantrelaTM
113
ER label33; RoxyBondTM label34). SAIB is commonly used in beverage as weighting agent, and
114
in lipstick as transfer resistant agent. It is a glassy liquid, water immiscible and highly lipophilic
115
molecule (log Pow is 6).35 Due to unique properties of the SAIB, addition of the excipient to the
116
formulation will improve abuse deterrent properties. The formulations were evaluated for surface
117
morphology, crystallinity, drug extraction in various solvents and dissolution, and compared with
118
formulations without SAIB.
119
MATERIALS AND METHODS
120
Materials
121
PSE was obtained from Sigma-Aldrich, St Louis, MO. Eastman Chemical Company, Kingsport,
122
TN provided BioSustane™ SAIB. MethocelTM K100M (HPMC) and PolyoxTM (PolyoxTM WSR-
Zephrex-D® and Nexafed® are based on proprietary
123
303, MW 7,000,000) was purchased from Colorcon, West point, PA. Microcrystalline cellulose
124
(MCC, Vivapur® 102) was obtained from JRS Pharma, Patterson, NY. Methanol, ethanol (200
125
proof), monobasic potassium phosphate, magnesium stearate (MGS), colloidal silicon dioxide
126
(CSD) and tocopherol acetate were purchased from Fisher Scientific, Asheville, NC. In-house
127
water (18 MΩ.cm, Millipore Milli-Q Gradient A-10 water purification system) was used in the
128
study.
129
Methods
130
Meth-Deterrent Formulations Preparation
131
Ethanolic solution of SAIB (90% w/w) was used as a granulating fluid. Formulation components
132
were granulated by two methods. Method 1: MethocelTM K100M and PolyoxTM WSR-303 were
133
granulated with SAIB solution containing tocopherol acetate to yield formulations A1 to A5.
134
Method 2: PSE, MethocelTM K100M and PolyoxTM WSR-303 were granulated with SAIB
135
solution containing tocopherol acetate to yield formulations A6 to A10. All components were
136
mixed in a V-blender (Model VH-2) and granulated in a high shear granulator (KG5, KEY
137
International Inc. NJ, USA). Granules were dried under the hood to a target loss on drying of
138
≤1% w/w. The granules were passed through a #20 sieve. The dried granules of formulations
139
A1-A5 were mixed with PSE, MCC, MGS and CSD while MCC, MGS and CSD were mixed
140
with the dried granules of formulations of A6-A10. Mixing was carried out for 2 min in a V-
141
blender. The granules were compressed into tablets using a Mini Press-1 (Globe Pharma, New
142
Brunswick, NJ, USA) 10-station tableting machine with 8 mm flat die and punches (Natoli
143
Engineering Company, Saint Charles, MO). Half of the tablets of each formulation were heat
144
cured in an oven at 90 oC for 30 min. Two control formulations (C1 and C2) were also prepared
145
without SAIB (Table 1). The uncured and cured formulations were characterized for surface
146
morphology, crystallinity, hardness, physical manipulation, particle size distribution, solvent
147
extraction, and dissolution.
148
Surface Morphology
149
Surface morphology of the formulations before and after heat curing was determined by
150
scanning electron microscopy (SEM, JSM-7500F, JEOL, Tokyo, Japan). Samples were
151
approximately coated with carbon to 5 nm thickness using a sputter coater (Cressington, 208 HR
152
with MTM-20 High Resolution Thickness Controller) under high vacuum (argon gas pressure
153
0.01 mbar) and high voltage of 40 mV. Morphology was captured at a working distance of 15
154
mm, an accelerated voltage of 5 KV and an emission current of 20 µA.
155
X-ray Powder Diffraction
156
XRPD patterns of the formulations were collected using a Bruker D2 Phaser SSD 160
157
Diffractometer (Bruker AXS, Madison, WI) equipped with the LYNXEYE scintillation detector
158
and Cu Kα radiation (λ= 1.54184 Å) at a voltage of 30 KV and a current of 10 mA. The samples
159
were prepared by evenly spreading the appropriate amount of powder on the sample holder. The
160
mounted samples were scanned over 2θ range of 5 to 30° at 1 s per step with an increment of
161
0.0202° and rotated at 15 rpm to get the average diffractogram. The collected data was evaluated
162
using Diffrac.EVA Suite version V4.2.1 and further processed using File Exchange 5.0 (Bruker
163
AXS, Madison, WI).
164
Mechanical Characterization
165
Hardness of tablets were measured using a texture analyzer (TA.XT Plus, Stable Micro Systems,
166
Surrey, UK). The equipment was fitted with 50 kg load cell. Texture analyzer hardness test
167
conditions were: compression mode, 2 mm/s pretest speed, 1 mm/s test speed, 10 mm/s post-test
168
speed, target mode-force, 491 N force, auto trigger and 1N trigger force. The measurements were
169
done in triplicate.
170
Particle Size Distribution
171
Meth-Deterrent formulations were powdered for 1 min.
172
Blender, Model#16249, Farberware, Fairfield, CA). The powder was passed through a size #18
173
sieve (pore opening size 1 mm) and the particle size distribution was measured
174
diffraction particle sizer (PSA 1190, Anton Paar, Ashland, VA). The data were collected at
175
following parameters: sample loading method venturi; vibrator duty 50%; vibrator frequency 45
176
Hz, air pressure 200 mBa; obscuration 0.5-1% and reconstruction mode Fraunhofer. Particles
177
size were expressed as D90 by volume.
178
Solvent Extraction
179
Drug extraction studies were performed on intact and powdered formulations in 100 ml water,
180
ethanol, 0.1 N HCl and 0.1 NaOH at room temperature. Intact tablet or powder equivalent to one
181
tablet was added to the solvent. A 100 µL sample was withdrawn at 5 min and 30 min.
in a coffee grinder (Single Serve
by laser
182
Extraction was also performed in 10 mL water at elevated temperature but below boiling point.
183
Drug extractions were carried out in an oven operated at 95 oC (Multifunction Drying/Heating
184
Oven with Forced Convection and timer, Model# FED 53 (E2), Binder, Bohemia, NY) and by
185
microwaving at 700 W (Model# HB-P90D23AP-ST, Hamilton Beach, Glen Allen, VA. Samples
186
were withdrawn at 5 and 10 min, and 5 and 10 sec from extraction studies involving oven and
187
microwave, respectively. Each experiment was performed in triplicate.
188
Dissolution
189
The USP basket method was used for dissolution studies (Model 708-DS with 850-DS
190
autosampler, Agilent Technologies, CA, USA). Each dissolution experiment was performed for
191
9 hours in 900 ml water at 100 rpm and 37 oC. A 1 mL sample was withdrawn and filtered
192
through nylon filters (0.45 µm, 25 mm). HPLC method was used to determine amount of
193
dissolved drug.
194
The method was developed and validated as per ICH guidance document.36 The equipment
195
consisted of Agilent 1260 series (Agilent Technologies, Wilmington, DE, US) which is equipped
196
with a quaternary pump, online degasser, column heater, autosampler and UV/Vis detector. Data
197
collection and analysis were performed using Openlab software (Agilent Technologies,
198
Wilmington, DE, US). Separation was achieved on a 4.6 x 250 mm, 5 µm Luna C18
199
(Phenomenex Torrance, CA, USA) column and a C18, 4.6x2.5 mm (5 µm packing) Luna C18
200
guard column (Phenomenex, Torrance, CA, USA). The elution was isocratic at 1.0 mL/min with
201
a mobile phase of methanol:buffer (pH 3.0) (70:30, v/v). The column temperature was
202
maintained at 30 °C in a column oven, and auto-sampler was maintained at 25 °C. The injection
203
volume was 10 µL, and detection was by UV at 214 nm.
204
RESULTS AND DISCUSSION
205
SEM
206
Photomicrographs (Figure 2) of uncured formulations indicated that surface of tablets were
207
relatively smooth with few cracks except for formulations A5 and A10 which contained 21.3%
208
SAIB. The surface of control formulation (C1) tablets were similar to those of samples A1 or A6.
209
There were significant differences between tablets of
210
formulation). The surface of A5 and A10 tablets were not as smooth as other formulations or
formulations A5, A10 and C2 (control
211
respective control formulation. This was probably due to the large amount of SAIB which
212
interfered with the compression compaction process. The number of cracks and crevices
213
increased after heat curing of the formulations. Curing was performed above the melting point of
214
PolyoxTM which caused fusion/bridge formation between particles and thus resulted in cracks
215
and crevices on the tablets surface.1,2
216
Crystallinity
217
Diffractograms of PSE and PolyoxTM indicated their crystalline nature. Major reflection peaks in
218
PSE were 7.0, 15.4, 17.2, 20.1, 20.9, 21.0 and 21.7o while PolyoxTM exhibited major peaks at
219
18.9 and 22o. The formulations exhibited peaks of the drug at 7.0, 15.4, 17.2, 20.1, 20.9 and
220
21.0o, and 18.9 and 22o peaks for PolyoxTM (figure 3). However, there were differences in drug
221
and polymer intensity peaks in the cured and uncured formulations. The intensity of drug peaks
222
increased while it decreased for PolyoxTM after heat curing. The increase in the intensity peaks of
223
the drug can be explained by generation of amorphous regions during compression and
224
subsequent devitrification during heat curing. Some fraction of the crystalline drug converts to
225
the amorphous form during the tableting process and then recrystallizes when heated below the
226
melting point of the drug.37-39 Decrease in peak intensity of the polymer can be explained by
227
melting and devitrification processes. On heat curing of the tablets, Polyox™ melts and
228
recrystallizes on cool down. However, the polymer was unable to regain initial crystallinity due
229
to insufficient time available to crystallize, and interference by other components of the
230
formulation.1,2 It is possible that the polymer can achieve its initial crystallinity during storage
231
but it will take long time.
232
Formulation Components Distribution
233
Formulation components distribution can be visualized by non-destructive NIR chemical
234
imaging technique. Hypercube data was mathematically treated by mean-centering and standard
235
normal variate before generating partial least squares (PLS) concentration images using library
236
components. The library was generated using SAIB, PSE and PolyoxTM. Red and blue pixels
237
indicate low and high concentration of specific component in the PLS concentration image,
238
which is generated using specific component of the library. The drug percentage was constant in
239
the test formulations that had 12.7% drug. The drug percentage was high in the control
240
formulations and varied form 13.7-16.2%. Pixels colors were yellowish-red with few pockets of
241
blue for drug distribution. Furthermore, pixels colors were relatively uniform for all the test
242
samples which indicated that test products contained similar amount of the drug (Figure 4A).
243
Control samples showed dark red pixels meaning the control formulation contained higher
244
amount of the drug than the test formulations. These pixels colors matched with actual amount of
245
the drug in the test and control formulations. The pixels colors for SAIB and PolyoxTM were
246
blue to greenish-yellow (Figure 4B) and yellowish-red to greenish-yellow (Figure 4C) which
247
indicated an increase in SAIB and a decrease in PolyoxTM amount in the formulations.
248
Percentage of SAIB and PolyoxTM were 7.1-21.3% and 24.8-32.0%, respectively for
249
formulations A1-A5. Thus, the change in pixel colors corresponds to the change in SAIB and
250
PolyoxTM percentage in the formulations.
251
Hardness
252
Hardness of tablets varied form 41.8±2.1 to 66.4±5.8 N for uncured test formulations (Figure 5).
253
Hardness of test formulations was comparable to control formulations, however, there was a
254
significant decrease in hardness when SAIB level in the formulations was more than 7.1%. The
255
difference in hardness between formulations containing low (A1 or A6) and high (A5 or A10)
256
level of SAIB varied form 7.1-20.8 N. Similarly, significant difference in hardness was observed
257
between formulations (A5 or A10) and control (C2) and values varied form 9.5-19.2 N. The
258
decrease in hardness of tablets was due to glassy-liquid nature of SAIB which interfered with
259
particle-particle contact during compression. There was a slight increase in hardness of the
260
formulations after heat curing, however, the increase in hardness was not significant. The
261
increase in mechanical properties of the tablets was due to PolyoxTM WSR-303. The melting
262
point range of Polyox™ polymer is reported to be 62–67 °C.40 Heat curing at 90 oC caused
263
melting of polymer, particles, fusion and bridge formation, which would increase the mechanical
264
strength of the formations. However, these formulations contains other components which would
265
interfere with particles fusion and bridge formation. The difference in tablet hardness between
266
test (A5 or A10) and control (C2) formulations did not change significantly after heat curing, but
267
remained in the range of 18.9-20.8 N.
268
Particle Size
269
Both uncured and cured tablets can be powdered in a coffee grinder (Single Serve Blender,
270
Model#16249, Farberware, Fairfield, CA) in a minute. The D90 of uncured formulations varied
271
from 273.7±7-370.1±22.1 µm. The formulations showed an increase in D90 values with an
272
increase in SAIB percentage in the formulations. Difference in D90 values between formulations
273
containing low (A1 or A6) and high (A5 or A10) percentage of SAIB was 82.0-96.4 µm.
274
Difference in D90 values was less than 10 µm between test (A1 or A5) and control formulations
275
(C1) when the test formulation contained 7.1% SAIB. However, D90 values difference between
276
test (A5 or A10) and control (C2) formulations was more than 107 µm when SAIB percentage
277
was 21.3%. An increase in particle size with an increase in SAIB percentage can be explained by
278
glassy nature of SAIB which impart elastic and adhesive properties to the powder mixture. The
279
value of D90 increased with heat curing of the formulations, and the values varied from 348.3-
280
387.0 µm. The increase was very significant at low percentage of SAIB compared to high
281
percentage of SAIB. The increase in D90 was more than 22.3-27.2% and 5.2-5.7% at low and
282
high percentage of SAIB after heat curing, respectively. The D90 difference between test
283
formulations containing low and high SAIB percentage was 37.8-42.8 µm after heat curing.
284
Similarly, D90 values difference between test (A5 or A10) and control formulations was 51.3-
285
56.4 (C2) µm (Figure 6).
286
Solvent extraction
287
PSE can be converted to MET by Birch, red phosphorous and one-pot methods. All the methods
288
required availability of PSE to be able to convert into MET.25 First step would be to extract the
289
drug from the formulation to proceed to next step of MET synthesis. Solvent extraction would
290
provide some assessment of the difficulty to synthesize MET from the formulations using
291
various solvents.
292
Water
293
The drug extraction from intact uncured formulations varied form 2.3-11.5% using water as a
294
solvent in 30 min at room temperature. The drug extraction decreased as the SAIB content
295
increased in the formulations. A decrease of 6.2-7.0% was observed when SAIB concentration
296
was increased from 7.1 to 21.3%. Addition of SAIB at 21.3% to formulations resulted 11.5-
297
13.7% decrease in the drug extraction. Heat curing of the formulations did not significantly
298
change the drug extraction. In fact, there was slight decrease in PSE extraction that could be
299
explained by an increase in mechanical property of the formulations. The difference in drug
300
extraction between test and control formulations was 10.4-11.7% at 21.3% SAIB. Difference
301
between test and control formulations was not significant when SAIB level was 7.1% for both
302
cured and uncured formulations (Figure 7A).
303
The extraction was 69.5-77.8% in uncured powder test formulations while it was 87.7-89.9% in
304
control formulations. The drug extraction was 6.6-6.7% higher in C1/C6 compared to C5/C10.
305
Significant difference in drug extraction was obtained between test and control formulations
306
containing low and high level of SAIB. The difference was 9.9-11.6% and 18.6-20.4% between
307
C1or C6 and C11, and C6 or C10 and C12. No significant difference in extraction was observed
308
between test formulations after heat curing. The difference in drug extraction between test and
309
control formulation decreased due to an increase in particle size especially in control
310
formulations after heat curing. The differences were 6.0-10.9% and 11.4-11.7% between test and
311
control formulations (Figure 7B).
312
Alcohol
313
The drug extraction was higher in alcohol compared with water, 0.1 N HCl or 0.1 N NaOH
314
solvent. The drug extraction varied from 11.1-35.2% from intact uncured formulations using
315
ethanol as an extracting solvent in 30 min. The drug extraction increased with an increase in
316
SAIB concentration in the formulations. For example, the drug extraction varied from 11.5-
317
12.9% and 28.6-35.0% at SAIB percentage of 7.1 and 21.3% in the formulations, respectively.
318
Drug extraction was significantly less in the control formulations compared with test
319
formulations. It was 5.7-7.0 and 17.4-23.8% less in the control formulations C1 and C2,
320
respectively, compared with corresponding test formulations (A1, A5, A6 and A10). Higher drug
321
extraction can be explained by solubility, tablet layering and non-gelling phenomenon. SAIB is
322
soluble while MethocelTM K100M and PolyoxTM are insoluble in ethanol. Ethanol dissolved
323
SAIB to form pores through which solvent can penetrate and extract the drug from interior
324
matrix. Literature reported that HPMC-based tablets layered in ethanol when HPMC content in
325
the tablets is 25-50% 1. The HMPC content in test formulation varied from 24.8-30.2%.
326
Furthermore, some of the tablets cracked after placing in alcohol which further increased solvent
327
penetration. PolyoxTM polymer does not form a gelling matrix in the alcohol. All these
328
phenomena explained higher extraction of the drug with alcohol. Drug extraction in cured intact
329
formulations varied form 12.1-36.8%. Drug extractions in cured formulations was slightly higher
330
than uncured formulations. Differences between test and control formulations were high. The
331
values varied form 7.4-9.1 and 21.6-26.0% between A1 or A6 and C1, and A5 or A10 and C2,
332
respectively. This could be explained due to surface morphology changes produced by heat
333
curing, which promote solvent penetration to dissolve SAIB, and resulted in higher extraction
334
(Figure 7C).
335
Drug extraction was >90% from powdered uncured and cured formulations. The values varied
336
from 90.3-106.5% and 95.7-107.0% for uncured and cured formulations, respectively. Curing
337
did not affect the drug extractions. The drug extraction differences between test and control
338
formulations decreased significantly after powdering. The difference in drug extraction between
339
test and control formulations was 4.5-7.8 and 4.4-11.7% for both cured and uncured formulations
340
at low and high level of SAIB, respectively (Figure 7D).
341
0.1 N HCl
342
Drug extraction was higher in acidic condition compared to water or 0.1 N NaOH. This could be
343
explained by pH dependent solubility of PSE. PSE is a basic molecule and hence exhibits high
344
solubility at acidic pH compared to alkaline pH.41 The drug extraction was 9.8-16.3% in the
345
intact uncured test formulations in 0.1 N HCl solvent. The drug extraction was less in the test
346
formulations compared to control formulations: 7.1-8.8% at an SAIB concentration of 21.3%.
347
However, no significant difference was observed between test and control formulations when
348
SAIB content was 7.1%. Drug extraction did not change significantly after heat curing of the
349
formulations. The values ranged from 11.0-16.7% after heat curing of the formulations (Figure
350
8A).
351
The drug extraction from powdered uncured formulations was 54.7-78.5%. Drug extraction
352
decreased with an increase in SAIB percentage in the formulations. The difference in drug
353
extraction between low and high percentage SAIB containing formulations was 21.6-22.3%. The
354
drug extraction was 31.6-33.9% less in test formulations (A5 or A10) compared to control
355
formulation (C2). No significant difference in drug extraction was observed between test and
356
control formulations when SAIB level was 7.1%. Curing of the formulations did not significantly
357
change drug extraction in test and control formulations compared to uncured formulations
358
(Figure 8B).
359
0.1 N NaOH
360
Drug extraction was slightly less in 0.1 N NaOH solvent compared to drug extraction in 0.1 N
361
HCl and water. This is related to low solubility of the drug at alkaline pH compared to drug
362
solubility at acidic pH.41 The values were 4.7-8.3% from intact uncured formulations in 30 min
363
at room temperature. There was 3.3-3.5% less drug extracted in the test formulations when SAIB
364
level was 21.3% compared to 7.1% SAIB. Compared to control formulation (C2), less than 4.8-
365
5.1% drug was extracted from test formulations (A5 or A10). If the SAIB level was less than
366
21.3%, no significant differences in drug extraction were observed in test formulations compared
367
to control formulation No significant effect of curing on the drug extraction were observed
368
(Figure 8C).
369
Using powdered uncured formulations, 54.7-78.5% drug can be extracted. The amount of
370
extracted drug decreased with an increase in SAIB percentage in the formulations. For example,
371
drug extraction was 65.1-69.0% and 48.9-53.4% when SAIB level was 7.1% and 21.3%,
372
respectively. The drug extraction in control formulations was 69.7-73.7%. On comparing test
373
(A5 or A10) and control (C2) formulations, the difference in drug extraction was 20.3-24.8%.
374
The difference in drug extraction between test and control formulations was similar in cured and
375
uncured formulations (Figure 8D).
376
Microwave and Oven
377
The amount of drug extracted can be increased using elevated temperatures (oven or
378
microwave). Drug extraction was performed for 10 sec and 15 min in microwave and oven,
379
respectively. Microwaving beyond 10 sec resulted in splattering. Oven temperature was set at 95
380
o
381
formulations. The amount of drug extracted from formulations containing low (7.1%) and high
382
(21.3%) content of SAIB was 5.0-5.6%. Differences between test formulations containing low
383
SAIB (7.1%) and control formulation were not significant. Additionally, the difference in drug
384
extraction was 5.8-6.1% between test formulation containing 21.3% SAIB and control
385
formulation. Heat curing had little effect on the amount of drug extracted. The drug extraction
386
was 5.9-11.5%, and the extraction difference were 4.7-5.5% between test and control
387
formulations from intact cured formulations (Figure 9A).
388
The dug extraction varied from 48.5-62.6% for uncured formulations when extracted using oven.
389
The extraction was significant between test formulations when SAIB percentage was 17.8% or
C. The drug extraction was 6.2-12.1% in 10 ml water using microwave from intact uncured
390
higher. The drug extraction difference between test formulations having low and high SAIB
391
percentage varied from 11.9-12.3%. The difference in drug extraction was 17.2-19.1% between
392
control and test formulations having high percentage of SAIB. No significant difference in drug
393
extraction was observed between test and control formulations at low SAIB percentage. Heat
394
curing of the formulations did not significantly change the drug extraction. The drug extraction
395
was 49.8-61.6% from intact cured formulations. The difference in drug extraction was 14.2-
396
15.8% between test (A5 or A10) and control (C2) formations. The difference was not significant
397
at low level of SAIB (Figure 9B).
398
The method of granulation did not significantly affect drug extraction in the studied solvents
399
from intact and powdered formulations.
400
Dissolution
401
Dissolution was more than 85% from uncured test formulations while it was more than 90%
402
from control formulations. Rate and extent of dissolution decreased with an increase in SAIB
403
content. This was related to water insolubility and hydrophobicity of SAIB. The dissolution
404
varied from 86.5-95.1% in nine hours. The dissolution rate and extent in control formulation
405
(C1) were very similar to test formulations (A1 or A6) containing low percentage (7.1%) of
406
SAIB. Difference in dissolution of 11.1-13.0% was obtained between test (A5 or A10) and
407
control (C2) formulations when SAIB level was 21.3% (Figure 10A). There was slight increase
408
in rate and extent of dissolution in both test and control formulations after heat curing of the
409
formulations (Figure 10B). This was possibly due to degradation of polymers present in the
410
formulations. PolyoxTM is known to degrade into smaller molecular fragment on heat curing.1,2,42
411
HPMC is also known to degrade on thermal exposure.43 Thermal degradation produced smaller
412
fragments of polymers with reduced viscosity and hence, less resistance to diffusion of drug
413
during dissolution process. The extent of drug dissolution was 86.9-97.3% from test formulations
414
after heat curing.
415
CONCLUSION
416
The PSE extraction and thus MET conversion can be reduced by using appropriate formulation
417
technology. Results indicated a significant reduction in the drug extraction which may be
418
translated into reduction in MET abuse. Addition of 21.3% SAIB to formulation resulted in at
419
least 11.4, 31.1 and 20.3% reduction in the drug extraction in water, 0.1 N HCl and 0.1 N NaOH,
420
respectively. SAIB did not decrease drug extraction in alcohol. It has negative effect on the
421
mechanical properties of the tablet at high percentage possibly by interfering in particle-particles
422
contact during compression. The dissolution was faster in control formulation without SAIB.
423
Addition of SAIB helps in modulating the dissolution as well.
424
ACKNOWLEDGEMENT
425
This work was supported by Eastman Chemicals Company, Kingsport, TN. The authors would
426
like to acknowledge Dr. Philip Cook for his valuable technical support.
427 428 429 430
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431
Cruz C, Ashraf M. Effects of excipients and curing process on the abuse deterrent
432
properties of directly compressed tablets. Int J Pharm. 2017;517:303-311.
433
2. Rahman Z, Yang Y, Korang-Yeboah M, Siddiqui A, Xu X, Ashraf M, Khan MA.
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Assessing impact of formulation and process variables on in-vitro performance of
435 436
directly compressed abuse deterrent formulations. Int J Pharm. 2016;502:138-50.
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3. Sansgiry SS, Bhansali AH, Bapat SS, Xu Q. Abuse of over-the-counter medicines: a pharmacist’s perspective. Integr Pharm Res Pract. 2017; 6:1–6. 4. ConsumerMedSafety.org. Top Ten OTC medicines and herbals abused by teens and
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young adults, 2014. Accessed on June 12, 2019. https://consumermedsafety.org/otc-drug-
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abuse/top-ten-otc-medicines-and-herbals-abused-by-teens-and-young-adults
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5. National Institute of Drug Abuse 2017. What are over-the-counter (OTC) medicines?
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counter-medicines
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6. Deckx L, Sutter AID, Guo L, Mir NA, van Driel ML. Nasal decongestants in monotherapy for the common cold.Cochrane Database Syst Rev. 2016;10: CD009612. 7. Freeman KB, Wang Z, Woolverton WL. Self-administration of (+)-methamphetamine
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and (+)-pseudoephedrine, alone and combined, by rhesus monkeys. Pharmacol Biochem
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Behav. 2010; 95:198-202.
449 450 451 452 453
8. Dobkin C, Nicosia N.The War on drugs: Methamphetamine, Public Health, and Crime. Am Econ Rev. 2009; 99:324-349. 9. Desoxyn® FDA label. Accessed on June 12, 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/005378s035lbl.pdf 10. Winterstein AG, Gerhard T, Kubilis P, Saidi A, Linden S, Crystal S, Zito J, Shuster JJ,
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Olfson M. Cardiovascular safety of central nervous system stimulants in children and
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adolescents: population based cohort study. BMJ. 2012;345:e4627.
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11. Chen LY, Strain EC, Alexandre PK, Alexander GC, Mojtabai R, Martins SS. Correlates
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of nonmedical use of stimulants and methamphetamine use in a national sample. Addict
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Behav. 2014;39:829–836.
460 461 462 463
12. Cooper RJ. Over-the-counter medicine abuse – a review of the literature. J Subst Use. 2013;18:82–107. 13. Narconon. The health risks of abusing pseudoephedrine. Accessed on June 12, 2019. https://www.narconon.org/drug-abuse/prescription/pseudoephedrine.html 14. Khazan M, Hedayati M, Kobarfard F, Askari S, Azizi F. Identification and determination
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of synthetic pharmaceuticals as adulterants in eight common herbal weight
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loss supplements. Iran Red Crescent Med J. 2014;16:e15344
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15. Yen M, Ewald MB. Toxicity of weight loss agents. J Med Toxicol. 2012;8:145–152.
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16. Gheorghiev MD, Hosseini F, Moran J, Cooper CE. Effects of pseudoephedrine on
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parameters affecting exercise performance: a meta-analysis. Sports Med Open. 2018;4:
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44.
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17. Reardon CL, Creado S. Drug abuse in athletes. Subst Abuse Rehabil. 2014;5:95–105
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18. Karpinos AR, Roumie CL, Nian H, Diamond AB, Rothman RL. High prevalence of
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hypertension among collegiate football athletes. Circ Cardiovasc Qual Outcomes.
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2013;6:716–723.
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19. Gill ND, Shield A, Blazevich AJ, Zhou S, Weatherby RP. Muscular and cardiorespiratory
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effects of pseudoephedrine in human athletes. Br J Clin Pharmacol. 2000;50: 205–213.
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20. Combat methamphetamine epidemic act of 2005. Diversion Control Division, Drug Enforcement Administration. Accessed on June 12, 2019. https://www.deadiversion.usdoj.gov/meth/index.html
479 480 481 482 483 484
21. Chemical Handler’s Manual- A guide to chemical control regulations, Drug Enforcement Administration, 2013. Accessed on June 12, 2019. https://www.deadiversion.usdoj.gov/pubs/manuals/chem/chem_manual.pdf 22. Gülhan B, Bayrakcı B, Babaoğlu MO, Bal B, Beken S. Biphasic creatine kinase elevation in pseudoephedrine overdosage. Br J Clin Pharmacol. 2009;67:139–140 23. Shao IH, Wu CC, Tseng HJ, Lee TJ, Lin YH, Tam YY. Voiding dysfunction in patients
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with nasal congestion treated with pseudoephedrine: a prospective study. Drug Des Devel
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Ther. 2016;10:2333–2339.
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24. Toxnet-Pseudoephedrine. Accessed on June 12, 2019. https://toxnet.nlm.nih.gov/cgibin/sis/search/a?dbs+hsdb:@term+@DOCNO+3177 25. Brzeczko AW, Leech R, BS, Stark JG. The advent of a new pseudoephedrine product to combat methamphetamine abuse. Am J Drug Alcohol Abuse. 2013;39:284–290.
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26. Nexafed Accessed on June 12, 2019. https://nexafed.com/consumer/products/
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27. Zephrex-D®. Accessed on June 12, 2019. http://zephrex-d.com/
494 495 496 497 498 499 500 501 502 503 504 505 506 507 508
28. Tarex® technology. Accessed on June 12, 2019. http://www.highlandpharma.com/tarextechnology 29. Impede® technology. Accessed on June 12, 2019. http://acurapharm.com/platforms/impede-technology/ 30. OxyContin® label. Accessed on June 11, 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/022272s034lbl.pdf 31. MorphaBond ERTM label. Accessed on June 11, 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/206544s002s005lbl.pdf 32. ArymoTM ER label. Accessed on June 11, 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208603s000lbl.pdf 33. VantrelaTM ER label. Accessed on June 11, 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/207975s000lbl.pdf 34. RoxyBondTM label. Accessed on June 11, 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209777lbl.pdf 35. BioSustane™ SAIB (Sucrose Acetate Isobutyrate), Technical data sheet. Eastman Chemical Company. Accessed 11 June 2019.
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https://productcatalog.eastman.com/tds/ProdDatasheet.aspx?product=71067382&pn=Bio Sustane+SAIB#_ga=2.259313539.824182645.1562601316-355059041.1485368602 36. ICH - validation of analytical procedures, text and methodology Q2(R1), 2005. 37. Togo T, Taniguchi T, Nakata Y. The Effect of compaction force on the transition to hydrate of anhydrous aripiprazole. chem. Pharm. Bull. 2018; 66:263–269. 38. Rahman Z, Siddiqui A, Khan MA. Assessing the impact of nimodipine devitrification in
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the ternary cosolvent system through quality by design approach. Int J Pharm.
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2013;455:113-23.
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39. Rahman Z, Agarabi C, Zidan AS, Khan SR, Khan MA. Physico-mechanical and stability
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evaluation of carbamazepine cocrystal with nicotinamide. AAPS PharmSciTech.
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2011;12:693-704.
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40. Polyox water-soluble resins dissolving techniques, 2003. Accessed on June 11, 2019.
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http://msdssearch.dow.com/PublishedLiteratureDOWCOM/dh_0046/0901b80380046565
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.pdf?filepath=polyox/pdfs/noreg/326-00002.pdf&fromPage=GetDoc
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41. Fairstein M, Swissa R, Dahan A. regional-dependent intestinal permeability and BCS classification: elucidation of pH-related complexity in rats using pseudoephedrine. AAPS J. 2013;15:589–597. 42. Xu X, Siddiqui A, Srinivasan C, Mohammad A, Rahman Z, Korang-Yeboah M, Feng X,
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Khan M, Ashraf M. Evaluation of abuse-deterrent characteristics of tablets prepared via
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hot-melt extrusion. AAPS PharmSciTech. 2019;20:230
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43. Meena A, Parikh T, Gupta SS, Serajuddin AT. Investigation of thermal and viscoelastic properties of polymers relevant to hot melt extrusion, II: Cellulosic polymers. J Excipients Food Chem. 2014;5:46–55.
538 539 540 541 542 543 544 545 546 547
Figures legend
548
Figure 1. Conversion of pseudoephedrine to methamphetamine by reduction process.
549
Figure 2. SEM images of cured and uncured test and control formulations.
550
Figure 3. X-ray powder diffractograms of PSE, PolyoxTM, uncured and cured formulations.
551
Figure 4. PLS concentration images showing distribution of A) PSE, B) SAIB and C) PolyoxTM
552
in the formulations.
553
Figure 5. Hardness data of uncured and cured formulations.
554
Figure 6. D90 data of uncured and cured formulations.
555
Figure 7. PSE extraction from A) intact and B) powdered formulation in 100 ml water, and C)
556
intact and D) powdered formulations in 100 ethanol at room temperature.
557
Figure 8. PSE extraction from A) intact and B) powdered formulation in 100 ml 0.1 N HCl, and
558
C) intact and D) powdered formulations in 100 0.1 N NaOH at room temperature.
559
Figure 9. PSE extraction from intact formulations in 10 ml water using A) microwave) and oven.
560
Figure 10. Dissolution profiles of A) uncured and B) cured formulations.
561 562 563
Table 1. Formulation composition Ingredients
Formulations C1-Control C2-Control 30 30 WSR75.5 58.7
A1/A6 30 16.8 75.5
A1/A7 30 25.2 71.3
A3/A8 A4/A9 30 30 33.6 41.9 67.1 62.9
A5/A10 30 50.3 58.7
PSE SAIB PolyoxTM 303 MethocelTM 75.5 58.7 75.5 71.3 67.1 62.9 58.7 K100M Tocopherol 0.2 0.2 0.2 0.2 0.2 0.2 0.2 acetate Microcrystalline 30 30 30 30 30 30 30 cellulose Magnesium 2 2 2 2 2 2 2 stearate Colloidal silicon 6 6 6 6 6 6 6 dioxide Total 219.2 185.6 236 236 236 236 236 A1-A5- Blend of PolyoxTM WSR-303 and MethocelTM K100M was granulated with ethanolic solution of SAIB and Tocopherol acetate A6-A10- A1-A5- Blend of PSE, PolyoxTM WSR-303 and MethocelTM K100M was granulated with ethanolic solution of SAIB and Tocopherol acetate
S0022-3549(19)30808-1
DOI:
https://doi.org/10.1016/j.xphs.2019.12.003
Reference:
XPHS 1819
To appear in:
Journal of Pharmaceutical Sciences
Received Date: 20 August 2019 Revised Date:
6 November 2019
Accepted Date: 3 December 2019
Please cite this article as: Dharani S, Barakh Ali SF, Afrooz H, Mohamed EM, Cook P, Khan MA, Rahman Z, Development Of Methamphetamine Abuse-Deterrent Formulations Using Sucrose Acetate Isobutyrate, Journal of Pharmaceutical Sciences (2020), doi: https://doi.org/10.1016/j.xphs.2019.12.003. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc. on behalf of the American Pharmacists Association.
1 2 3
DEVELOPMENT OF METHAMPHETAMINE ABUSE-DETERRENT FORMULATIONS USING SUCROSE ACETATE ISOBUTYRATE
4
Sathish Dharani1, Sogra F. Barakh Ali1, Hamideh Afrooz1, Eman M. Mohamed1,2, Phillip Cook3,
5
Mansoor A. Khan1, Ziyaur Rahman1*
6
1-Irma Lerma Rangel College of Pharmacy, Texas A&M Health Science Center, Texas A&M
7
University, College Station, TX 77843, USA
8
2-Department of Pharmaceutics, Faculty of Pharmacy, Beni-Suef University, Egypt.
9
3-Eastman Chemical Company, Kingsport, TN 37662, USA
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34
*-Corresponding author Ziyaur Rahman, Ph.D. Associate Professor 310 Reynolds Medical Sciences Building College Station, Texas 77843-1114 Email: [email protected] Phone: 979-436-0873 Fax: 979-436-0087
35
ABSTRACT
36
The objective of the present research was to investigate application of sucrose acetate isobutyrate
37
(SAIB) in the development of a Meth-Deterrent formulation in combination with polyethylene
38
oxide (PolyoxTM) and hydroxypropyl methylcellulose (HPMC). The formulations were
39
prepared by granulating pseudoephedrine hydrochloride (PSE), HPMC and PolyoxTM with an
40
ethanolic solution of SAIB and compressed into tablets followed by heat curing. The tablets were
41
characterized for surface morphology, crystallinity, drug distribution, hardness, particle size,
42
extraction, and dissolution. Hardness increased insignificantly, surface morphology indicated
43
cracking and crevices, and diffractograms showed an increase and a decrease in drug and
44
PolyoxTM crystallinity, respectively, after heat curing. PSE, PolyoxTM and SAIB distribution
45
was uniform as indicated by NIR image. The drug extraction varied from 69.5-77.8, 90.3-106.5,
46
51.3-81.2 and 48.9-72.6% in water, ethanol, 0.1 N HCl and 0.1 N NaOH, respectively. The
47
dissolution was more than 85% in 9 hours from all the formulations. Thus, the addition of SAIB
48
to the formulation decreased the drug extraction in various solvents which has the potential to
49
decrease abuse of pseudoephedrine formulation for methamphetamine synthesis.
50
Key words: Meth-Deterrent formulations, Pseudoephedrine hydrochloride, PolyoxTM, HPMC,
51
solvent extraction, dissolution, Sucrose acetate isobutyrate, SAIB
52 53 54 55 56 57 58 59 60 61
62
INTRODUCTION
63
The United States has a serious problem of drug abuse which leads to social, economic and
64
medical issues.1,2 Abusers can abuse prescription and over-the-counter (OTC) drug products. It
65
is much easier and inexpensive to get over-the counter (OTC) than prescription medicines. OTC
66
drug products are available in supermarkets, drugstores and convenience stores. There is
67
widespread but wrong belief that these drugs must be less dangerous than those found behind the
68
pharmacy counter because one need a prescription. The top ten OTC drug products abused by
69
teens and adults are dextromethorphan, loperamide, pain relievers (acetaminophen and
70
ibuprofen), caffeine medicines and energy drinks (NoDoz and 5 Hour Energy), diet pills
71
(stimulant found in diet pills are phenylpropanolamine, ephedrine, and ephedra), laxative and
72
herbal diuretics (water pills, includes uva-ursa, golden seal, dandelion root, rose hips, and others
73
to lose weight), motion sickness pills (dimenhydrinate (Dramamine) or diphenhydramine
74
(Benadryl)), sexual performance medicines, pseudoephedrine hydrochloride (PSE), herbal
75
ecstasy (the main ingredient is ma huang (ephedra) and other herbal e.g. Salvia, Nutmeg).3-5
76
Since they are legal and easy to find, OTC drugs are also easy to abuse. Abuse of OTC
77
medicines is most common among teens between the ages of 13 and 16.4 They know they can
78
find a cheap "high" right in their family's or friend's medicine cabinet. Young adults have also
79
abused OTC medicines, particularly in combination with other medicines, alcohol, and illegal
80
drugs, which increases the risks of serious side effects.3-5
81
PSE is a nasal decongestant and stimulant, and commonly found in many cold medicines e.g.
82
Sudogest and Nexafed etc.6 It can be diverted to synthesize methamphetamine (MET), a potent
83
stimulant and addictive compound. Its chemical structure is similar to amphetamine. PSE
84
(C10H15NO) and MET (C10H15N) differ by oxygen atom which can be removed by chemical
85
reduction reaction
86
with hyperactivity and exogenous obesity, and is commercially available as a tablet dosage
87
form.9 It is abused as a central nervous system stimulant to cause an excitable, hyperactive
88
feeling.10,11 However, PSE can also be abused without chemical conversion to MET.12,13 People
89
have taken PSE to lose weight,14,15 and athletes have misused the medicine to increase their state
90
of awareness and to get them “pumped up” before a competition.16-19 Abuse of PSE is low
91
compared to other OTC products due to federal law requiring it to be kept behind the pharmacy
92
counter, limiting the purchase quantity, and requiring photo identification prior to purchase.20
7,8
(Figure 1). MET has been approved by FDA for attentive deficit disorder
93
Additionally, Drug Enforcement Administration classified PSE under “List I of chemicals” to
94
further control diversion and misuse of PSE.21 Dangerous side effects of PSE include heart
95
palpitations, irregular heartbeats, and heart attacks. When combined with other drugs, such as
96
narcotics, PSE may trigger episodes of paranoid psychosis.22-24 Unlike opioids addiction/toxicity
97
treatment, there is no antidote for PSE or MET addiction/toxicity treatment.
98
To further cut down the access of pseudoephedrine from the pharmacy and hence reduce the
99
conversion of PSE into MET, pharmaceutical manufacturer(s) have developed novel
100
formulations called Meth-Deterrent formulations, which are a type of abuse deterrent
101
formulations.25 Currently, there are three PSE commercial products with Meth-Deterrent claim:
102
Nexafed®26 (PSE, Nasal decongestant), Nexafed®26 (PSE and acetaminophen, Sinus pressure +
103
Pain) and Zephrex-D®27 (PSE, sinus pressure). However, the FDA has not approved nor
104
endorsed Meth-Deterrent claims.
105
technologies called Tarex® and Impede®, respectively. Tarex® is based on lipid formulation
106
which provides resistance to PSE extraction (Tarex® technology)28. On the other hands, Impede®
107
is based on polymers matrix which forms a viscous mass when it comes in contact with aqueous
108
medium (Impede® technology)29. The objective of the present research was to investigate abuse
109
deterrent properties of Meth-Deterrent formulations based on polyethylene oxide (PolyoxTM) and
110
hydroxypropyl methyl cellulose (HPMC) with and without sucrose acetate isobutyrate
111
(BioSustane™, SAIB).25 PolyoxTM and HPMC are commonly found in opioid abuse-deterrent
112
formulations (OxyContin® label30; MorphaBond ERTM label31; ArymoTM ER label32; VantrelaTM
113
ER label33; RoxyBondTM label34). SAIB is commonly used in beverage as weighting agent, and
114
in lipstick as transfer resistant agent. It is a glassy liquid, water immiscible and highly lipophilic
115
molecule (log Pow is 6).35 Due to unique properties of the SAIB, addition of the excipient to the
116
formulation will improve abuse deterrent properties. The formulations were evaluated for surface
117
morphology, crystallinity, drug extraction in various solvents and dissolution, and compared with
118
formulations without SAIB.
119
MATERIALS AND METHODS
120
Materials
121
PSE was obtained from Sigma-Aldrich, St Louis, MO. Eastman Chemical Company, Kingsport,
122
TN provided BioSustane™ SAIB. MethocelTM K100M (HPMC) and PolyoxTM (PolyoxTM WSR-
Zephrex-D® and Nexafed® are based on proprietary
123
303, MW 7,000,000) was purchased from Colorcon, West point, PA. Microcrystalline cellulose
124
(MCC, Vivapur® 102) was obtained from JRS Pharma, Patterson, NY. Methanol, ethanol (200
125
proof), monobasic potassium phosphate, magnesium stearate (MGS), colloidal silicon dioxide
126
(CSD) and tocopherol acetate were purchased from Fisher Scientific, Asheville, NC. In-house
127
water (18 MΩ.cm, Millipore Milli-Q Gradient A-10 water purification system) was used in the
128
study.
129
Methods
130
Meth-Deterrent Formulations Preparation
131
Ethanolic solution of SAIB (90% w/w) was used as a granulating fluid. Formulation components
132
were granulated by two methods. Method 1: MethocelTM K100M and PolyoxTM WSR-303 were
133
granulated with SAIB solution containing tocopherol acetate to yield formulations A1 to A5.
134
Method 2: PSE, MethocelTM K100M and PolyoxTM WSR-303 were granulated with SAIB
135
solution containing tocopherol acetate to yield formulations A6 to A10. All components were
136
mixed in a V-blender (Model VH-2) and granulated in a high shear granulator (KG5, KEY
137
International Inc. NJ, USA). Granules were dried under the hood to a target loss on drying of
138
≤1% w/w. The granules were passed through a #20 sieve. The dried granules of formulations
139
A1-A5 were mixed with PSE, MCC, MGS and CSD while MCC, MGS and CSD were mixed
140
with the dried granules of formulations of A6-A10. Mixing was carried out for 2 min in a V-
141
blender. The granules were compressed into tablets using a Mini Press-1 (Globe Pharma, New
142
Brunswick, NJ, USA) 10-station tableting machine with 8 mm flat die and punches (Natoli
143
Engineering Company, Saint Charles, MO). Half of the tablets of each formulation were heat
144
cured in an oven at 90 oC for 30 min. Two control formulations (C1 and C2) were also prepared
145
without SAIB (Table 1). The uncured and cured formulations were characterized for surface
146
morphology, crystallinity, hardness, physical manipulation, particle size distribution, solvent
147
extraction, and dissolution.
148
Surface Morphology
149
Surface morphology of the formulations before and after heat curing was determined by
150
scanning electron microscopy (SEM, JSM-7500F, JEOL, Tokyo, Japan). Samples were
151
approximately coated with carbon to 5 nm thickness using a sputter coater (Cressington, 208 HR
152
with MTM-20 High Resolution Thickness Controller) under high vacuum (argon gas pressure
153
0.01 mbar) and high voltage of 40 mV. Morphology was captured at a working distance of 15
154
mm, an accelerated voltage of 5 KV and an emission current of 20 µA.
155
X-ray Powder Diffraction
156
XRPD patterns of the formulations were collected using a Bruker D2 Phaser SSD 160
157
Diffractometer (Bruker AXS, Madison, WI) equipped with the LYNXEYE scintillation detector
158
and Cu Kα radiation (λ= 1.54184 Å) at a voltage of 30 KV and a current of 10 mA. The samples
159
were prepared by evenly spreading the appropriate amount of powder on the sample holder. The
160
mounted samples were scanned over 2θ range of 5 to 30° at 1 s per step with an increment of
161
0.0202° and rotated at 15 rpm to get the average diffractogram. The collected data was evaluated
162
using Diffrac.EVA Suite version V4.2.1 and further processed using File Exchange 5.0 (Bruker
163
AXS, Madison, WI).
164
Mechanical Characterization
165
Hardness of tablets were measured using a texture analyzer (TA.XT Plus, Stable Micro Systems,
166
Surrey, UK). The equipment was fitted with 50 kg load cell. Texture analyzer hardness test
167
conditions were: compression mode, 2 mm/s pretest speed, 1 mm/s test speed, 10 mm/s post-test
168
speed, target mode-force, 491 N force, auto trigger and 1N trigger force. The measurements were
169
done in triplicate.
170
Particle Size Distribution
171
Meth-Deterrent formulations were powdered for 1 min.
172
Blender, Model#16249, Farberware, Fairfield, CA). The powder was passed through a size #18
173
sieve (pore opening size 1 mm) and the particle size distribution was measured
174
diffraction particle sizer (PSA 1190, Anton Paar, Ashland, VA). The data were collected at
175
following parameters: sample loading method venturi; vibrator duty 50%; vibrator frequency 45
176
Hz, air pressure 200 mBa; obscuration 0.5-1% and reconstruction mode Fraunhofer. Particles
177
size were expressed as D90 by volume.
178
Solvent Extraction
179
Drug extraction studies were performed on intact and powdered formulations in 100 ml water,
180
ethanol, 0.1 N HCl and 0.1 NaOH at room temperature. Intact tablet or powder equivalent to one
181
tablet was added to the solvent. A 100 µL sample was withdrawn at 5 min and 30 min.
in a coffee grinder (Single Serve
by laser
182
Extraction was also performed in 10 mL water at elevated temperature but below boiling point.
183
Drug extractions were carried out in an oven operated at 95 oC (Multifunction Drying/Heating
184
Oven with Forced Convection and timer, Model# FED 53 (E2), Binder, Bohemia, NY) and by
185
microwaving at 700 W (Model# HB-P90D23AP-ST, Hamilton Beach, Glen Allen, VA. Samples
186
were withdrawn at 5 and 10 min, and 5 and 10 sec from extraction studies involving oven and
187
microwave, respectively. Each experiment was performed in triplicate.
188
Dissolution
189
The USP basket method was used for dissolution studies (Model 708-DS with 850-DS
190
autosampler, Agilent Technologies, CA, USA). Each dissolution experiment was performed for
191
9 hours in 900 ml water at 100 rpm and 37 oC. A 1 mL sample was withdrawn and filtered
192
through nylon filters (0.45 µm, 25 mm). HPLC method was used to determine amount of
193
dissolved drug.
194
The method was developed and validated as per ICH guidance document.36 The equipment
195
consisted of Agilent 1260 series (Agilent Technologies, Wilmington, DE, US) which is equipped
196
with a quaternary pump, online degasser, column heater, autosampler and UV/Vis detector. Data
197
collection and analysis were performed using Openlab software (Agilent Technologies,
198
Wilmington, DE, US). Separation was achieved on a 4.6 x 250 mm, 5 µm Luna C18
199
(Phenomenex Torrance, CA, USA) column and a C18, 4.6x2.5 mm (5 µm packing) Luna C18
200
guard column (Phenomenex, Torrance, CA, USA). The elution was isocratic at 1.0 mL/min with
201
a mobile phase of methanol:buffer (pH 3.0) (70:30, v/v). The column temperature was
202
maintained at 30 °C in a column oven, and auto-sampler was maintained at 25 °C. The injection
203
volume was 10 µL, and detection was by UV at 214 nm.
204
RESULTS AND DISCUSSION
205
SEM
206
Photomicrographs (Figure 2) of uncured formulations indicated that surface of tablets were
207
relatively smooth with few cracks except for formulations A5 and A10 which contained 21.3%
208
SAIB. The surface of control formulation (C1) tablets were similar to those of samples A1 or A6.
209
There were significant differences between tablets of
210
formulation). The surface of A5 and A10 tablets were not as smooth as other formulations or
formulations A5, A10 and C2 (control
211
respective control formulation. This was probably due to the large amount of SAIB which
212
interfered with the compression compaction process. The number of cracks and crevices
213
increased after heat curing of the formulations. Curing was performed above the melting point of
214
PolyoxTM which caused fusion/bridge formation between particles and thus resulted in cracks
215
and crevices on the tablets surface.1,2
216
Crystallinity
217
Diffractograms of PSE and PolyoxTM indicated their crystalline nature. Major reflection peaks in
218
PSE were 7.0, 15.4, 17.2, 20.1, 20.9, 21.0 and 21.7o while PolyoxTM exhibited major peaks at
219
18.9 and 22o. The formulations exhibited peaks of the drug at 7.0, 15.4, 17.2, 20.1, 20.9 and
220
21.0o, and 18.9 and 22o peaks for PolyoxTM (figure 3). However, there were differences in drug
221
and polymer intensity peaks in the cured and uncured formulations. The intensity of drug peaks
222
increased while it decreased for PolyoxTM after heat curing. The increase in the intensity peaks of
223
the drug can be explained by generation of amorphous regions during compression and
224
subsequent devitrification during heat curing. Some fraction of the crystalline drug converts to
225
the amorphous form during the tableting process and then recrystallizes when heated below the
226
melting point of the drug.37-39 Decrease in peak intensity of the polymer can be explained by
227
melting and devitrification processes. On heat curing of the tablets, Polyox™ melts and
228
recrystallizes on cool down. However, the polymer was unable to regain initial crystallinity due
229
to insufficient time available to crystallize, and interference by other components of the
230
formulation.1,2 It is possible that the polymer can achieve its initial crystallinity during storage
231
but it will take long time.
232
Formulation Components Distribution
233
Formulation components distribution can be visualized by non-destructive NIR chemical
234
imaging technique. Hypercube data was mathematically treated by mean-centering and standard
235
normal variate before generating partial least squares (PLS) concentration images using library
236
components. The library was generated using SAIB, PSE and PolyoxTM. Red and blue pixels
237
indicate low and high concentration of specific component in the PLS concentration image,
238
which is generated using specific component of the library. The drug percentage was constant in
239
the test formulations that had 12.7% drug. The drug percentage was high in the control
240
formulations and varied form 13.7-16.2%. Pixels colors were yellowish-red with few pockets of
241
blue for drug distribution. Furthermore, pixels colors were relatively uniform for all the test
242
samples which indicated that test products contained similar amount of the drug (Figure 4A).
243
Control samples showed dark red pixels meaning the control formulation contained higher
244
amount of the drug than the test formulations. These pixels colors matched with actual amount of
245
the drug in the test and control formulations. The pixels colors for SAIB and PolyoxTM were
246
blue to greenish-yellow (Figure 4B) and yellowish-red to greenish-yellow (Figure 4C) which
247
indicated an increase in SAIB and a decrease in PolyoxTM amount in the formulations.
248
Percentage of SAIB and PolyoxTM were 7.1-21.3% and 24.8-32.0%, respectively for
249
formulations A1-A5. Thus, the change in pixel colors corresponds to the change in SAIB and
250
PolyoxTM percentage in the formulations.
251
Hardness
252
Hardness of tablets varied form 41.8±2.1 to 66.4±5.8 N for uncured test formulations (Figure 5).
253
Hardness of test formulations was comparable to control formulations, however, there was a
254
significant decrease in hardness when SAIB level in the formulations was more than 7.1%. The
255
difference in hardness between formulations containing low (A1 or A6) and high (A5 or A10)
256
level of SAIB varied form 7.1-20.8 N. Similarly, significant difference in hardness was observed
257
between formulations (A5 or A10) and control (C2) and values varied form 9.5-19.2 N. The
258
decrease in hardness of tablets was due to glassy-liquid nature of SAIB which interfered with
259
particle-particle contact during compression. There was a slight increase in hardness of the
260
formulations after heat curing, however, the increase in hardness was not significant. The
261
increase in mechanical properties of the tablets was due to PolyoxTM WSR-303. The melting
262
point range of Polyox™ polymer is reported to be 62–67 °C.40 Heat curing at 90 oC caused
263
melting of polymer, particles, fusion and bridge formation, which would increase the mechanical
264
strength of the formations. However, these formulations contains other components which would
265
interfere with particles fusion and bridge formation. The difference in tablet hardness between
266
test (A5 or A10) and control (C2) formulations did not change significantly after heat curing, but
267
remained in the range of 18.9-20.8 N.
268
Particle Size
269
Both uncured and cured tablets can be powdered in a coffee grinder (Single Serve Blender,
270
Model#16249, Farberware, Fairfield, CA) in a minute. The D90 of uncured formulations varied
271
from 273.7±7-370.1±22.1 µm. The formulations showed an increase in D90 values with an
272
increase in SAIB percentage in the formulations. Difference in D90 values between formulations
273
containing low (A1 or A6) and high (A5 or A10) percentage of SAIB was 82.0-96.4 µm.
274
Difference in D90 values was less than 10 µm between test (A1 or A5) and control formulations
275
(C1) when the test formulation contained 7.1% SAIB. However, D90 values difference between
276
test (A5 or A10) and control (C2) formulations was more than 107 µm when SAIB percentage
277
was 21.3%. An increase in particle size with an increase in SAIB percentage can be explained by
278
glassy nature of SAIB which impart elastic and adhesive properties to the powder mixture. The
279
value of D90 increased with heat curing of the formulations, and the values varied from 348.3-
280
387.0 µm. The increase was very significant at low percentage of SAIB compared to high
281
percentage of SAIB. The increase in D90 was more than 22.3-27.2% and 5.2-5.7% at low and
282
high percentage of SAIB after heat curing, respectively. The D90 difference between test
283
formulations containing low and high SAIB percentage was 37.8-42.8 µm after heat curing.
284
Similarly, D90 values difference between test (A5 or A10) and control formulations was 51.3-
285
56.4 (C2) µm (Figure 6).
286
Solvent extraction
287
PSE can be converted to MET by Birch, red phosphorous and one-pot methods. All the methods
288
required availability of PSE to be able to convert into MET.25 First step would be to extract the
289
drug from the formulation to proceed to next step of MET synthesis. Solvent extraction would
290
provide some assessment of the difficulty to synthesize MET from the formulations using
291
various solvents.
292
Water
293
The drug extraction from intact uncured formulations varied form 2.3-11.5% using water as a
294
solvent in 30 min at room temperature. The drug extraction decreased as the SAIB content
295
increased in the formulations. A decrease of 6.2-7.0% was observed when SAIB concentration
296
was increased from 7.1 to 21.3%. Addition of SAIB at 21.3% to formulations resulted 11.5-
297
13.7% decrease in the drug extraction. Heat curing of the formulations did not significantly
298
change the drug extraction. In fact, there was slight decrease in PSE extraction that could be
299
explained by an increase in mechanical property of the formulations. The difference in drug
300
extraction between test and control formulations was 10.4-11.7% at 21.3% SAIB. Difference
301
between test and control formulations was not significant when SAIB level was 7.1% for both
302
cured and uncured formulations (Figure 7A).
303
The extraction was 69.5-77.8% in uncured powder test formulations while it was 87.7-89.9% in
304
control formulations. The drug extraction was 6.6-6.7% higher in C1/C6 compared to C5/C10.
305
Significant difference in drug extraction was obtained between test and control formulations
306
containing low and high level of SAIB. The difference was 9.9-11.6% and 18.6-20.4% between
307
C1or C6 and C11, and C6 or C10 and C12. No significant difference in extraction was observed
308
between test formulations after heat curing. The difference in drug extraction between test and
309
control formulation decreased due to an increase in particle size especially in control
310
formulations after heat curing. The differences were 6.0-10.9% and 11.4-11.7% between test and
311
control formulations (Figure 7B).
312
Alcohol
313
The drug extraction was higher in alcohol compared with water, 0.1 N HCl or 0.1 N NaOH
314
solvent. The drug extraction varied from 11.1-35.2% from intact uncured formulations using
315
ethanol as an extracting solvent in 30 min. The drug extraction increased with an increase in
316
SAIB concentration in the formulations. For example, the drug extraction varied from 11.5-
317
12.9% and 28.6-35.0% at SAIB percentage of 7.1 and 21.3% in the formulations, respectively.
318
Drug extraction was significantly less in the control formulations compared with test
319
formulations. It was 5.7-7.0 and 17.4-23.8% less in the control formulations C1 and C2,
320
respectively, compared with corresponding test formulations (A1, A5, A6 and A10). Higher drug
321
extraction can be explained by solubility, tablet layering and non-gelling phenomenon. SAIB is
322
soluble while MethocelTM K100M and PolyoxTM are insoluble in ethanol. Ethanol dissolved
323
SAIB to form pores through which solvent can penetrate and extract the drug from interior
324
matrix. Literature reported that HPMC-based tablets layered in ethanol when HPMC content in
325
the tablets is 25-50% 1. The HMPC content in test formulation varied from 24.8-30.2%.
326
Furthermore, some of the tablets cracked after placing in alcohol which further increased solvent
327
penetration. PolyoxTM polymer does not form a gelling matrix in the alcohol. All these
328
phenomena explained higher extraction of the drug with alcohol. Drug extraction in cured intact
329
formulations varied form 12.1-36.8%. Drug extractions in cured formulations was slightly higher
330
than uncured formulations. Differences between test and control formulations were high. The
331
values varied form 7.4-9.1 and 21.6-26.0% between A1 or A6 and C1, and A5 or A10 and C2,
332
respectively. This could be explained due to surface morphology changes produced by heat
333
curing, which promote solvent penetration to dissolve SAIB, and resulted in higher extraction
334
(Figure 7C).
335
Drug extraction was >90% from powdered uncured and cured formulations. The values varied
336
from 90.3-106.5% and 95.7-107.0% for uncured and cured formulations, respectively. Curing
337
did not affect the drug extractions. The drug extraction differences between test and control
338
formulations decreased significantly after powdering. The difference in drug extraction between
339
test and control formulations was 4.5-7.8 and 4.4-11.7% for both cured and uncured formulations
340
at low and high level of SAIB, respectively (Figure 7D).
341
0.1 N HCl
342
Drug extraction was higher in acidic condition compared to water or 0.1 N NaOH. This could be
343
explained by pH dependent solubility of PSE. PSE is a basic molecule and hence exhibits high
344
solubility at acidic pH compared to alkaline pH.41 The drug extraction was 9.8-16.3% in the
345
intact uncured test formulations in 0.1 N HCl solvent. The drug extraction was less in the test
346
formulations compared to control formulations: 7.1-8.8% at an SAIB concentration of 21.3%.
347
However, no significant difference was observed between test and control formulations when
348
SAIB content was 7.1%. Drug extraction did not change significantly after heat curing of the
349
formulations. The values ranged from 11.0-16.7% after heat curing of the formulations (Figure
350
8A).
351
The drug extraction from powdered uncured formulations was 54.7-78.5%. Drug extraction
352
decreased with an increase in SAIB percentage in the formulations. The difference in drug
353
extraction between low and high percentage SAIB containing formulations was 21.6-22.3%. The
354
drug extraction was 31.6-33.9% less in test formulations (A5 or A10) compared to control
355
formulation (C2). No significant difference in drug extraction was observed between test and
356
control formulations when SAIB level was 7.1%. Curing of the formulations did not significantly
357
change drug extraction in test and control formulations compared to uncured formulations
358
(Figure 8B).
359
0.1 N NaOH
360
Drug extraction was slightly less in 0.1 N NaOH solvent compared to drug extraction in 0.1 N
361
HCl and water. This is related to low solubility of the drug at alkaline pH compared to drug
362
solubility at acidic pH.41 The values were 4.7-8.3% from intact uncured formulations in 30 min
363
at room temperature. There was 3.3-3.5% less drug extracted in the test formulations when SAIB
364
level was 21.3% compared to 7.1% SAIB. Compared to control formulation (C2), less than 4.8-
365
5.1% drug was extracted from test formulations (A5 or A10). If the SAIB level was less than
366
21.3%, no significant differences in drug extraction were observed in test formulations compared
367
to control formulation No significant effect of curing on the drug extraction were observed
368
(Figure 8C).
369
Using powdered uncured formulations, 54.7-78.5% drug can be extracted. The amount of
370
extracted drug decreased with an increase in SAIB percentage in the formulations. For example,
371
drug extraction was 65.1-69.0% and 48.9-53.4% when SAIB level was 7.1% and 21.3%,
372
respectively. The drug extraction in control formulations was 69.7-73.7%. On comparing test
373
(A5 or A10) and control (C2) formulations, the difference in drug extraction was 20.3-24.8%.
374
The difference in drug extraction between test and control formulations was similar in cured and
375
uncured formulations (Figure 8D).
376
Microwave and Oven
377
The amount of drug extracted can be increased using elevated temperatures (oven or
378
microwave). Drug extraction was performed for 10 sec and 15 min in microwave and oven,
379
respectively. Microwaving beyond 10 sec resulted in splattering. Oven temperature was set at 95
380
o
381
formulations. The amount of drug extracted from formulations containing low (7.1%) and high
382
(21.3%) content of SAIB was 5.0-5.6%. Differences between test formulations containing low
383
SAIB (7.1%) and control formulation were not significant. Additionally, the difference in drug
384
extraction was 5.8-6.1% between test formulation containing 21.3% SAIB and control
385
formulation. Heat curing had little effect on the amount of drug extracted. The drug extraction
386
was 5.9-11.5%, and the extraction difference were 4.7-5.5% between test and control
387
formulations from intact cured formulations (Figure 9A).
388
The dug extraction varied from 48.5-62.6% for uncured formulations when extracted using oven.
389
The extraction was significant between test formulations when SAIB percentage was 17.8% or
C. The drug extraction was 6.2-12.1% in 10 ml water using microwave from intact uncured
390
higher. The drug extraction difference between test formulations having low and high SAIB
391
percentage varied from 11.9-12.3%. The difference in drug extraction was 17.2-19.1% between
392
control and test formulations having high percentage of SAIB. No significant difference in drug
393
extraction was observed between test and control formulations at low SAIB percentage. Heat
394
curing of the formulations did not significantly change the drug extraction. The drug extraction
395
was 49.8-61.6% from intact cured formulations. The difference in drug extraction was 14.2-
396
15.8% between test (A5 or A10) and control (C2) formations. The difference was not significant
397
at low level of SAIB (Figure 9B).
398
The method of granulation did not significantly affect drug extraction in the studied solvents
399
from intact and powdered formulations.
400
Dissolution
401
Dissolution was more than 85% from uncured test formulations while it was more than 90%
402
from control formulations. Rate and extent of dissolution decreased with an increase in SAIB
403
content. This was related to water insolubility and hydrophobicity of SAIB. The dissolution
404
varied from 86.5-95.1% in nine hours. The dissolution rate and extent in control formulation
405
(C1) were very similar to test formulations (A1 or A6) containing low percentage (7.1%) of
406
SAIB. Difference in dissolution of 11.1-13.0% was obtained between test (A5 or A10) and
407
control (C2) formulations when SAIB level was 21.3% (Figure 10A). There was slight increase
408
in rate and extent of dissolution in both test and control formulations after heat curing of the
409
formulations (Figure 10B). This was possibly due to degradation of polymers present in the
410
formulations. PolyoxTM is known to degrade into smaller molecular fragment on heat curing.1,2,42
411
HPMC is also known to degrade on thermal exposure.43 Thermal degradation produced smaller
412
fragments of polymers with reduced viscosity and hence, less resistance to diffusion of drug
413
during dissolution process. The extent of drug dissolution was 86.9-97.3% from test formulations
414
after heat curing.
415
CONCLUSION
416
The PSE extraction and thus MET conversion can be reduced by using appropriate formulation
417
technology. Results indicated a significant reduction in the drug extraction which may be
418
translated into reduction in MET abuse. Addition of 21.3% SAIB to formulation resulted in at
419
least 11.4, 31.1 and 20.3% reduction in the drug extraction in water, 0.1 N HCl and 0.1 N NaOH,
420
respectively. SAIB did not decrease drug extraction in alcohol. It has negative effect on the
421
mechanical properties of the tablet at high percentage possibly by interfering in particle-particles
422
contact during compression. The dissolution was faster in control formulation without SAIB.
423
Addition of SAIB helps in modulating the dissolution as well.
424
ACKNOWLEDGEMENT
425
This work was supported by Eastman Chemicals Company, Kingsport, TN. The authors would
426
like to acknowledge Dr. Philip Cook for his valuable technical support.
427 428 429 430
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27. Zephrex-D®. Accessed on June 12, 2019. http://zephrex-d.com/
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28. Tarex® technology. Accessed on June 12, 2019. http://www.highlandpharma.com/tarextechnology 29. Impede® technology. Accessed on June 12, 2019. http://acurapharm.com/platforms/impede-technology/ 30. OxyContin® label. Accessed on June 11, 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/022272s034lbl.pdf 31. MorphaBond ERTM label. Accessed on June 11, 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/206544s002s005lbl.pdf 32. ArymoTM ER label. Accessed on June 11, 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208603s000lbl.pdf 33. VantrelaTM ER label. Accessed on June 11, 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/207975s000lbl.pdf 34. RoxyBondTM label. Accessed on June 11, 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209777lbl.pdf 35. BioSustane™ SAIB (Sucrose Acetate Isobutyrate), Technical data sheet. Eastman Chemical Company. Accessed 11 June 2019.
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https://productcatalog.eastman.com/tds/ProdDatasheet.aspx?product=71067382&pn=Bio Sustane+SAIB#_ga=2.259313539.824182645.1562601316-355059041.1485368602 36. ICH - validation of analytical procedures, text and methodology Q2(R1), 2005. 37. Togo T, Taniguchi T, Nakata Y. The Effect of compaction force on the transition to hydrate of anhydrous aripiprazole. chem. Pharm. Bull. 2018; 66:263–269. 38. Rahman Z, Siddiqui A, Khan MA. Assessing the impact of nimodipine devitrification in
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the ternary cosolvent system through quality by design approach. Int J Pharm.
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2013;455:113-23.
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39. Rahman Z, Agarabi C, Zidan AS, Khan SR, Khan MA. Physico-mechanical and stability
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evaluation of carbamazepine cocrystal with nicotinamide. AAPS PharmSciTech.
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2011;12:693-704.
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40. Polyox water-soluble resins dissolving techniques, 2003. Accessed on June 11, 2019.
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http://msdssearch.dow.com/PublishedLiteratureDOWCOM/dh_0046/0901b80380046565
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.pdf?filepath=polyox/pdfs/noreg/326-00002.pdf&fromPage=GetDoc
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41. Fairstein M, Swissa R, Dahan A. regional-dependent intestinal permeability and BCS classification: elucidation of pH-related complexity in rats using pseudoephedrine. AAPS J. 2013;15:589–597. 42. Xu X, Siddiqui A, Srinivasan C, Mohammad A, Rahman Z, Korang-Yeboah M, Feng X,
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Khan M, Ashraf M. Evaluation of abuse-deterrent characteristics of tablets prepared via
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hot-melt extrusion. AAPS PharmSciTech. 2019;20:230
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43. Meena A, Parikh T, Gupta SS, Serajuddin AT. Investigation of thermal and viscoelastic properties of polymers relevant to hot melt extrusion, II: Cellulosic polymers. J Excipients Food Chem. 2014;5:46–55.
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Figures legend
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Figure 1. Conversion of pseudoephedrine to methamphetamine by reduction process.
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Figure 2. SEM images of cured and uncured test and control formulations.
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Figure 3. X-ray powder diffractograms of PSE, PolyoxTM, uncured and cured formulations.
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Figure 4. PLS concentration images showing distribution of A) PSE, B) SAIB and C) PolyoxTM
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in the formulations.
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Figure 5. Hardness data of uncured and cured formulations.
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Figure 6. D90 data of uncured and cured formulations.
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Figure 7. PSE extraction from A) intact and B) powdered formulation in 100 ml water, and C)
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intact and D) powdered formulations in 100 ethanol at room temperature.
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Figure 8. PSE extraction from A) intact and B) powdered formulation in 100 ml 0.1 N HCl, and
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C) intact and D) powdered formulations in 100 0.1 N NaOH at room temperature.
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Figure 9. PSE extraction from intact formulations in 10 ml water using A) microwave) and oven.
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Figure 10. Dissolution profiles of A) uncured and B) cured formulations.
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Table 1. Formulation composition Ingredients
Formulations C1-Control C2-Control 30 30 WSR75.5 58.7
A1/A6 30 16.8 75.5
A1/A7 30 25.2 71.3
A3/A8 A4/A9 30 30 33.6 41.9 67.1 62.9
A5/A10 30 50.3 58.7
PSE SAIB PolyoxTM 303 MethocelTM 75.5 58.7 75.5 71.3 67.1 62.9 58.7 K100M Tocopherol 0.2 0.2 0.2 0.2 0.2 0.2 0.2 acetate Microcrystalline 30 30 30 30 30 30 30 cellulose Magnesium 2 2 2 2 2 2 2 stearate Colloidal silicon 6 6 6 6 6 6 6 dioxide Total 219.2 185.6 236 236 236 236 236 A1-A5- Blend of PolyoxTM WSR-303 and MethocelTM K100M was granulated with ethanolic solution of SAIB and Tocopherol acetate A6-A10- A1-A5- Blend of PSE, PolyoxTM WSR-303 and MethocelTM K100M was granulated with ethanolic solution of SAIB and Tocopherol acetate