Development of a microparticle-based dry powder inhalation formulation of ciprofloxacin hydrochloride applying the quality by design approach

Figures & data

Table 1 Composition of the DPI products containing an optimal concentration of excipients

No	CIP (g)	LEU (g)	PVA (g)	CD (g)	Solvent (mL)
1	1	–	–	–	50
2	1	–	0.2	–	50
3	1	–	–	0.9	50
4	1	0.4	–	–	50
5	1	0.4	0.2	0.9	50

Abbreviations: DPI, dry powder inhalation; PVA, polyvinyl alcohol; CIP, ciprofloxacin hydrochloride; LEU, l-leucine; CD, cyclodextrin.

Table 2 Büchi Mini Dryer B-191 parameters for spray-drying procedure

Inlet temperature (°C)	Outlet temperature (°C)	Feed rate (mL·min^−1)	Aspiration air (L·h^−1)	Aspiration rate (L·min^−1)
130	75	5	600	0.065

Figure 1 Ishikawa diagram illustrating the parameters influencing the quality of the ciprofloxacin-containing DPI product.

Abbreviations: DPI, dry powder inhalation; FPF, fine particle fraction; MMAD, mass median aerodynamic diameter; LEU, l-leucine; FT-IR, Fourier-transform infrared spectroscopy; PVA, polyvinyl alcohol.

Table 3 Selected QTPPs, CQAs, and CPPs of a ciprofloxacin-containing DPI formula, their target, justification, and explanation

	Target	Justification/explanation
QTPPs
Therapeutic indication	Antibiotic (respiratory tract infections)	Antibacterial therapy is essential in respiratory tract infections. Ciprofloxacin is a second-generation fluoroquinolone antibiotic with a broad spectrum of activity. It is especially effective against infections caused by Gram-negative bacteria
Target patient population	Adults	Literature data support a wide use of fluoroquinolone antibiotics in adults. It is a pregnancy category C antibiotic, considered to be safe during breastfeeding. It is also allowed for pediatric therapy but is never a first-line choice
		Target patient group, as QTPP affects the dose selection and the route of administration
Route of administration	Pulmonary administration	A relatively new route of administration for local antibacterial therapy. Pulmonary application avoids the first-pass effect and reduces systemic exposure and the risk of side effects
Site of activity	Local effect	Producing a local effect in pulmonary infections allows dose reduction of the antibiotics, associated with a lower risk of side effects Preselection of the desired site of activity as QTPP affects the API used, as well as the dose and the dosage form selected
Dosage form	Dry powder for pulmonary use	Dry powders with a particle size of 2–4 μm are required for the optimal deposition in lungs Predetermination of the adequate dosage form is a QTPP according to the ICH Q8 guideline
Dissolution profile	Increased dissolution	Dissolution profile is a recommended QTPP as it affects the bioavailability and pharmacokinetics and is critically related to the quality, safety, and efficacy of the medicinal product
CQAs
Excipients (quality profile)	Excipients assure proper quality characteristics by modifying the size, morphology, hydrophilicity, and stability of the DPI product	Polyvinyl alcohol 3-88 is a microfine coating material The amino acid l-leucine can be well co-spray-dried with certain active compounds to modify the drug’s aerolization behavior Dimethyl-beta cyclodextrin can be applied as a drug distribution enhancer As CQAs, excipients are critically related to the dissolution and quality profile of the final product
Particle size/specific surface area (SSA)	Homogeneous, microsized product of 2–4 μm	Microsize dimension has the optimal specific surface area and optimal administration properties for pulmonary use Size is critically related to pulmonary administration and to its local and/or systemic therapeutic effect, thereby to product safety, efficacy, and quality
Appearance	Microparticle	Microparticle formulation is suitable to achieve an increased SSA, an improved wettability, and a high amount of dissolved drug It is critically related to efficacy
Dissolution	Improved dissolution rate (100% in 5 min)	The dissolution profile highly affects the therapeutic effect. Accelerated drug release induces an immediate local effect. It is related to the modification of the SSA, wettability, and solubility
Wettability	Hydrophyl product	Wettability is critical for the drug’s adhesion the pulmonary mucosa. It is critically related to efficacy
Structure (crystalline/amorphous)	Stable form (crystalline/amorphous)	The crystalline or the amorphous state of the API affects stability and release properties. It is critically related to efficacy and quality
Solubility	Water-soluble	Solubility has a remarkable influence on the bioavailability of the drug/product
CPPs
Composition (co-spray drying)	Micronized size, stabilized structure using additives	Additives contribute to reaching the desired and predefined quality of the final co-spray-dried product
Inlet temperature (co-spray drying)	130°C	Inlet temperature has a critical influence on optimal drying and thus influences the final product’s appearance
Outlet temperature (co-spray drying)	75°C	Outlet temperature has a critical influence on optimal drying of the desired co-spray-dried final product
Feed rate (co-spray drying)	5 mL⋅min^−1	Feed rate has a critical influence on the formation of co-micronized particles

Abbreviations: QTPPs, quality target product profiles; CQAs, critical quality attributes; CPPs, critical process parameters; DPI, dry powder inhalation.

Figure 2 Results of (A) the interdependence rating of the QTPPs and CQAs and of the CPPs and CQAs, (B) the occurrence rating of the CPPs, and (C) Pareto charts of the CQAs and CPPs with calculated numeric severity scores generated by the RA software.

Abbreviations: QTPPs, quality target product profiles; CQAs, critical quality attributes; CPPs, critical process parameters; RA, risk assessment.

Table 4 Particle size of the microparticles of various compositions prepared

Material	D(0.1) µm	D(0.5) µm	D(0.9) µm	Specific surface (m^2·g^−1)
CIP_SPD	1.31±0.01	2.44±0.02	4.44±0.01	2.76±0.03
CIP_PVA_SPD	1.22±0.04	2.38±0.03	4.57±0.03	2.85±0.02
CIP_CD_SPD	1.68±0.03	3.02±0.06	5.24±0.04	2.20±0.09
CIP_LEU_SPD	1.62±0.05	2.84±0.02	4.84±0.00	2.33±0.01
CIP_PVA_CD_LEU_SPD	1.58±0.06	3.27±0.01	6.42±0.02	2.14±0.02

Abbreviations: PVA, polyvinyl alcohol; CIP, ciprofloxacin hydrochloride; LEU, l-leucine; CD, cyclodextrin; SPD, spray drying.

Figure 3 Scanning electron micrographs of the spray-dried microparticles.

Abbreviations: CIP, ciprofloxacin hydrochloride; SPD, spray drying; RAW, unattended material; CD, cyclodextrin; LEU, l-leucine; PVA, polyvinyl alcohol.

Figure 4 Thermograms of raw CIP and of the different CIP-containing microparticles investigated.

Abbreviations: CIP, ciprofloxacin hydrochloride; SPD, spray drying; RAW, unattended material; CD, cyclodextrin; LEU, l-leucine; PVA, polyvinyl alcohol.

Figure 5 XRPD diffractograms of raw CIP and of the CIP-containing microparticle compositions investigated.

Abbreviations: XRPD, X-ray powder diffraction; CIP, ciprofloxacin hydrochloride; SPD, spray drying; RAW, unattended material; CD, cyclodextrin; LEU, l-leucine; PVA, polyvinyl alcohol.

Figure 6 FT-IR spectra of ciprofloxacin hydrochloride (CIP) and the CIP-containing microparticle compositions investigated.

Abbreviations: FT-IR, Fourier-transform infrared spectroscopy; SPD, spray drying; RAW, unattended material; CD, cyclodextrin; LEU, l-leucine; PVA, polyvinyl alcohol.

Table 5 Drug content, fine particle fraction (FPF), mass median aerodynamic diameter (MMAD), and emitted dose (ED) of the CIP-containing microparticle compositions investigated

DPI	Drug content (%)	FPF (%)	MMAD (µm)	ED (%)
CIP_SPD	100±0	31.68±1.4	7.23±0.01	99.95±0.5
CIP_PVA_SPD	85±0.07	60.18±1.3	3.61±0.05	95.92±0.4
CIP_CD_SPD	59±0.03	58.54±1.1	3.19±0.01	96.93±0.5
CIP_LEU_SPD	72±0.08	80.27±1.7	2.15±0.08	95.81±0.6
CIP_PVA_CD_LEU_SPD	45±0.24	45.93±1.4	4.53±0.02	97.68±0.4

Abbreviations: PVA, polyvinyl alcohol; CIP, ciprofloxacin hydrochloride; LEU, l-leucine; CD, cyclodextrin; SPD, spray drying.

Table 6 Maximum measured concentration of ciprofloxacin hydrochloride filtered saturated solution

Solvent	pH	Concentration (mg·mL^−1)	λ max (nm)
Buffer solution	7.4	6.3	271
Distilled water	4.4	41.9	275

Figure 7 Kinetic plots of free ciprofloxacin release from the microparticles investigated.

Abbreviations: CIP, ciprofloxacin hydrochloride; SPD, spray drying; CD, cyclodextrin; LEU, l-leucine; PVA, polyvinyl alcohol.